STING agonistic compound

ABSTRACT

A drug or agent containing a compound having an agonistic activity to STING as an active ingredient, where the compound is represented by the following general formula (I-1): 
                         
wherein all symbols represent the same meanings as described in the specification, and the compound can be used as an active ingredient of an agent for suppressing the progression of, suppressing the recurrence of and/or treating cancer or infectious disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Phase Entry of PCT InternationalApplication No. PCT/JP2019/039941, filed Oct. 10, 2019, which claimspriority from Japanese Patent Application No. 2018-192276 filed on Oct.11, 2018.

TECHNICAL FIELD

The present invention relates a compound represented by the generalformula (i):

[wherein, all symbols have the same meanings as described below.], anN-oxide thereof, a prodrug thereof, a pharmaceutically acceptable saltthereof or a solvate thereof, and a compound represented by the generalformula (I-1):

[wherein, all symbols have the same meanings as described below.], anN-oxide thereof, a pharmaceutically acceptable salt thereof, or asolvate thereof (hereinafter, these compounds may be described as “thecompound of the present invention”), and a pharmaceutical compositioncontaining any one of these compounds as an active ingredient, andpharmaceutical uses thereof.

BACKGROUND ART

It is known that STING (Stimulation of Interferon Genes) is anendoplasmic reticulum localized type four-transmembrane protein and isinvolved in innate immunity. When foreign double-stranded DNAs appear incytoplasm due to infection or the like, cyclic GMP-AMP synthase (cGAS)is activated and cyclic GMP-AMP (cGAMP) is synthesized. This cGAMP bindsto STING on endoplasmic reticulum and induces type I interferon (IFN)production. On the other hand, it is known that cyclic dinucleotidessuch as cyclic Di-GMP, which were first identified as a second messengerof bacteria and later confirmed to also exist in mammals, also directlybind to STING and activate it (Non-Patent Literature 1).

Furthermore, STING is also known to be involved in autoimmune diseasesand tumor immunity. For example, it has been indicated that abnormalhost DNAs leak from the nucleus and activate STING to inducepro-inflammatory responses, which have been implicated in autoimmunedisease. The STING pathway also detects tumor-derived DNAs and promotesT cell responses to tumors. It is known that a STING agonistic compoundadministered to mouse tumors induces adaptive immune response to causetumor regression (Non-Patent Literature 2), and that an activatingmolecule of the STING pathway enhances IFN production and exhibitsantiviral effects. (Non-Patent Literature 3).

Heretofore, as STING agonist compounds, the compounds which areso-called cyclic dimerized nucleic acids as disclosed in PatentLiteratures 1 to 3 and non-cyclic dimerized nucleic acids as disclosedin Patent Literatures 4 to 7 have been reported. However, no SUNGagonist compound having a structure like the compound of the presentinvention has been reported.

CITATION LIST Patent Literature

-   Patent Literature 1: International Publication No. 2017/093933-   Patent Literature 2: International Publication No. 2017/186711-   Patent Literature 3: International Publication No. 2017/106740-   Patent Literature 4: International Publication No. 2017/175156-   Patent Literature 5: US Patent Application Publication No.    2017/0050967 Publication-   Patent Literature 6: US Patent Application Publication No.    2017/0146519 Publication-   Patent Literature 7: International Publication No. 2018/067423

Non-Patent Literature

-   Non-Patent Literature 1: Devaux L. et. al., Curr. Opi. Microbiol.    41, 21-28 (2018)-   Non-Patent Literature 2: Corrales L. et. al., Cell Rep. 11 (7),    1018-1030 (2015)-   Non-Patent Literature 3: Sail T. M. et. al., PLoS Pathog., 11 (12):    el 005324

SUMMARY OF INVENTION Technical Problem

The object of the present invention is to provide a drug containing acompound having agonistic activity to STING as an active ingredient.

Solution to Problem

The present inventors have conducted extensive studies to find compoundshaving agonistic activity to STING, and as a result, found the followingcompounds and then completed the present invention.

That is, the present invention is as follows.

[1] A compound represented by the general formula (I):

[wherein, X and Y represent —CH or a nitrogen atom (provided that both Xand Y do not represent —CH═, simultaneously), respectively, Z representsan oxygen atom or sulfur atom, T represents a carbon atom or nitrogenatom, Ring A represents a 5 to 7-membered monocycle, Ring B represents a5 to 7-membered monocycle or 8 to 10-membered bicycle, L¹ represents abond, —O—, —CONH—, —CO—, —CO₂—, —S—, —SO₂— or —SO—, L² represents abond, C1-3 alkylene group, C3-7 cycloalkylene group or phenylene group,R¹ represents a hydrogen atom, halogen atom, hydroxyl group, cyanogroup, N(R^(1a))₂ (herein, two R^(1a)s represent each independently ahydrogen atom or C1-4 alkyl group), C1-4 alkyl group, carboxy group,C1-4 alkoxycarbonyl group, C1-4 haloalkyl group, methyl-d₃ group, C3-7cycloalkyl group, phenyl group or 3 to 7-membered monocyclicnon-aromatic heterocycle, R² represents a hydrogen atom, halogen atom,hydroxyl group, oxo group, nitro group, cyano group. C1-4 alkoxy groupor —CH₂NR^(2a)R^(2b) or NR^(2a)R^(2b) (herein, R^(2a) represents ahydrogen atom or C1-4 alkyl group, R^(2b) represents a hydrogen atom), mrepresents an integer of 0 or 1, R¹ represents a hydrogen atom, halogenatom, hydroxyl group, C1-4 alkyl group, C1-4 alkoxy group. C1-4haloalkyl group, C1-4 haloalkoxy group or amino group, and n representsan integer of 1 to 16 (herein, when n is two or more, the groupsrepresented by a plurality of R³s may be the same or different), R⁴represents a hydrogen atom, C1-4 alkyl group or carboxy group, and R⁵represents a C1-4 alkyl group, p represents an integer of 0 to 5(herein, when p is 2 or more, the groups represented by a plurality ofR⁵s may be the same or different), and R⁶ represents a hydrogen atom orC1-4 alkyl group, R⁷ is a hydrogen atom. Further, b represents thebonding position of Ring B.], an N-oxide thereof, a prodrug thereof, apharmaceutically acceptable salt thereof, or a solvate thereof;[2] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof, or solvate thereof, according to the precedingitem [1], wherein Ring A is (a) a C5-6 monocyclic carbocycle or (b) a 5to 6-membered monocyclic heterocycle containing 1 to 4 heteroatomsselected from an oxygen atom, nitrogen atom and sulfur atom;[3] the compound, N-oxide (hereof, prodrug thereof, pharmaceuticallyacceptable salt thereof, or solvate thereof, according to the precedingitem [1] or [2], wherein Ring B is (a) a C5-6 monocyclic carbocycle or(b) a 5 to 6-membered monocyclic heterocycle containing 1 to 4heteroatoms selected from an oxygen atom, nitrogen atom and sulfur atom;[4] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof, or solvate thereof, according to the precedingitem [1] or [3], wherein Ring A is (a) a benzene ring or (b) a 5 to6-membered monocyclic aromatic heterocycle containing 1 to 4 heteroatomsselected from an oxygen atom, nitrogen atom and sulfur atom;[5] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof, or solvate thereof, according to any one of thepreceding items [1], [2] and [4], wherein Ring B is (a) a benzene ringor (b) a 5 to 6-membered monocyclic aromatic heterocycle containing 1 to4 heteroatoms selected from an oxygen atom, nitrogen atom and sulfuratom;[6] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof, or solvate thereof, according to any one of thepreceding items [1], [3] and [5], wherein Ring A is a 5 to 6-memberedmonocyclic aromatic nitrogen-containing heterocycle containing 1 to 4nitrogen atoms, without any other heteroatoms;[7] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof, or solvate thereof, according to any one of thepreceding items [1] to [6], wherein Z is an oxygen atom;[8] the compound, N-oxide (hereof, prodrug thereof, pharmaceuticallyacceptable salt thereof, or solvate thereof, according to any one of thepreceding items [1] to [7], wherein X is a nitrogen atom, and Y is —CH—;[9] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof, or solvate thereof, according to any one of thepreceding items [1] to [8], wherein

[wherein, the arrow is bound to the carbon atom represented by b in thegeneral formula (I), and other symbols represent the same meanings asdescribed above.] of the general formula (I) is the group represented bythe following formula (Ib):

[wherein, U represents a nitrogen atom or carbon atom (herein, when Urepresents a nitrogen atom, m represents 0, and when U represents acarbon atom, m represents 1), W represents —CR³═ or a nitrogen atom, Vrepresents —CH═ or a nitrogen atom, and when the formula (Ib) has aplurality of R³s, the groups represented by them may be the same ordifferent and other symbols represent the same meaning as describedabove.];[10] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof, or solvate thereof, according to the precedingitem [1], wherein the compound represented by the general formula (I) isthe compound represented by the general formula (II)

[wherein, all symbols have the same meanings as described above.];[11] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [10], wherein T is a nitrogen atom;[12] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [9] to [11], wherein U is a carbon atom;[13] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1], [3], [5] and [7] to [12], wherein Ring A ispyrazole, triazole (e.g., 1,2,3-triazole and 1,2,4-triazole), tetrazole,oxazole, isoxazole, imidazole, thiazole or isothiazole;[14] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to the precedingitem [1], wherein the compound represented by the general formula (I) isthe compound represented by the general formula (III):

[wherein, pa represents an integer of 0 to 2, and other symbolsrepresent the same meanings as described above.];[15] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [14], wherein L² in the general formula (I),general formula (II) and general formula (III) (hereinafter, may beabbreviated as “the general formula (I) or the like”) is a bond or C1-3alkylene group;[16] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [15], wherein L¹ in the general formula (I) orthe like is —O—, —CONH—, —CO—, —CO₂—, —S—, —SO₂— or —SO—;[17] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [15], wherein L¹ in the general formula (I) orthe like is —CONH— (provided that the left side of the group is bound toRing B), —CO—, —CO₂—, —S—, —SO₂— or —SO—;[18] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [17], wherein R¹ is a hydrogen atom, hydroxylgroup, C1-4 alkyl group or carboxy group;[19] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [17], wherein R¹ is a hydrogen atom or C1-4 alkylgroup;[20] the compound, N-oxide thereof, prodrug (hereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [19], wherein R² is a nitro group orNR^(2a)R^(2b);[21] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [20], wherein both of R^(2a) and R^(2b) arehydrogen atoms;[22] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [21], wherein R³ is a hydrogen atom, halogen atomor hydroxyl group;[23] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [22], wherein R⁴ is a hydrogen atom;[24] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [23], wherein R⁶ is a hydrogen atom;[25] the compound, N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to any one of thepreceding items [1] to [24], wherein p and pa are zero or 1;[26] the compound. N-oxide thereof, prodrug thereof, pharmaceuticallyacceptable salt thereof or solvate thereof, according to the precedingitem [1], wherein the compound represented by the general formula (I) isthe compound selected from the group consisting of:

-   (1)    4-(4-amino-2-fluoro-5-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[5,4-e]pyridin-3-amine,-   (2)    4-(4-amino-2-fluoro-5-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,-   (3)    4-(4-amino-3-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,-   (4)    4-(4-amino-2-fluoro-5-(methylthio)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,-   (5)    4-(4-amino-2-fluoro-5-(methoxy-d₃)phenyl)-7-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,-   (6)    4-(4-amino-2-fluoro-5-(methylsulfonyl)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,    -   (7)        4-(4-amino-5-(ethylthio)-2-fluorophenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,-   (8)    4-(4-amino-2-fluoro-5-(methylsulfonyl)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,-   (9)    4-(4-amino-2-fluoro-3-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-e]pyridin-3-amine.-   (10) methyl    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate,-   (11)    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoic    acid,-   (12)    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzamide,-   (13)    4-(4-amino-2-fluoro-5-methoxyphenyl)-7-(3-methyl-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,-   (14)    1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-r]pyridin-4-yl)-4-fluorophenyl)ethan-1-one,-   (15)    4-(4-amino-2-chloro-5-(methylthio)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,-   (16) ethyl    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate,-   (17)    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluoro-N-methylbenzamide,-   (18)    1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)propan-1-one,-   (19)    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-ethyl-4-fluorobenzamide,-   (20)    1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)phenyl)ethan-1-one,-   (21) methyl    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)benzoate,-   (22)    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-propylbenzamide,-   (23)    1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)butan-1-one, (24)    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluoro-N-propylbenzamide,-   (25)    1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)phenyl)butan-1-one,-   (26) 2-hydroxyethyl    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate,-   (27)    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)benzamide,-   (28)    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-methylbenzamide,-   (29)    1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-hydroxyphenyl)ethan-1-one,-   (30) 2-amino-5-(3-amino-7-(1    W-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-ethylbenzamide,-   (31)    1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)phenyl)propan-1-one,-   (32)    2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-chloro-N-ethylbenzamide,-   (33)    4-(2-fluoro-5-methoxy-4-nitrophenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,-   (34)    1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isothiazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)ethan-1-one,    and-   (35)    4-(4-amino-2-fluoro-5-(trifluoromethyl)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine;    [1-1] a compound represented by the general formula (I-1):

[wherein, R^(2c) represents a hydrogen atom, hydroxyl group, halogenatom, oxo group, nitro group, cyano group. C1-4 alkoxy group or—CH₂NR^(2d)R^(2e) or NR^(2d)R^(2e) (herein, R^(2d) is a hydrogen atom,C1-4 alkyl group or R^(FR), and R^(2e) represents a hydrogen atom),R^(4a) represents a hydrogen atom. C1-4 alkyl group, carboxy group orR^(FR), R^(6a) represents a hydrogen atom. C1-4 alkyl group or R^(FR),and R^(FR) represents:(i) —(CR^(Fb) ₂)_(q)OP(═O)(OR^(Fa))₂ [wherein, R^(Fa) represents eachindependently a hydrogen atom, C1-4 alkyl group, C3-6 cycloalkyl group,—(CH₂)₂OH or —CH₂OCO₂CH(CH₃)₂, R^(Fb) represents a hydrogen atom ormethyl group, and q represents an integer of 1 or 2 (herein, the groupsrepresented by a plurality of R^(Fb)s may be the same or different).](hereinafter, the group —(CR^(Fb) ₂)_(q)OP(═O)(OR^(Fa))₂ may becollectively referred to as a “phosphonooxyalkyl group”), or(ii) a free radical group producing a compound represented by thegeneral formula (I), N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, as a result of decomposition in vivo, andother symbols represent the same meanings as defined above, providedthat two or more of R^(2d), R^(4a) and R^(6a) do not represent R^(FR),simultaneously.], an N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof;[1-2] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to the preceding item [1-1],wherein Ring A is (a) a C5-6 monocyclic carbocycle or (b) a 5 to6-membered monocyclic heterocycle containing 1 to 4 heteroatoms selectedfrom an oxygen atom, nitrogen atom and sulfur atom;[1-3] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to the preceding item [1-1] or[1-2], wherein Ring B is (a) a C5-6 monocyclic carbocycle or (b) a 5 to6-membered monocyclic heterocycle containing 1 to 4 heteroatoms selectedfrom an oxygen atom, nitrogen atom and sulfur atom;[1-4] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to the preceding item [1-1] or[1-3], wherein Ring A is (a) a benzene ring or (b) a 5 to 6-memberedmonocyclic aromatic heterocycle containing 1 to 4 heteroatoms selectedfrom an oxygen atom, nitrogen atom and sulfur atom;[1-S] the compound, N-oxide thereof, pharmaceutically acceptable salt(hereof or solvate thereof, according to any one of the preceding items[1-1], [1-2] and [1-4], wherein Ring B is (a) a benzene ring or (b) a 5to 6-membered monocyclic aromatic heterocycle containing 1 to 4heteroatoms selected from an oxygen atom, nitrogen atom and sulfur atom;[1-6] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1], [1-3] and [1-5], wherein Ring A is a 5 to 6-membered monocyclicaromatic nitrogen-containing heterocycle containing 1 to 4 nitrogenatoms, without any other heteroatoms;[1-7] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-6], wherein Z is an oxygen atom;[1-8] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-7], wherein X is a nitrogen atom and Y is —CH═;[1-9] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof, or solvate thereof, according to any one of the preceding items[1-1] to [1-8], wherein

[wherein, the arrow is bound to the carbon atom represented by b in thegeneral formula (I-1), and other symbols represent the same meanings asdescribed above.] of the general formula (I-1) is the group representedby the formula (Ib-1):

[wherein, all symbols represent the same meaning as described above.];[1-10] the compound, N-oxide (hereof, pharmaceutically acceptable saltthereof, or solvate thereof, according to the preceding item [1-1],wherein the compound represented by the general formula (I-1) is thecompound represented by the general formula (II-1):

[wherein, all symbols represent the same meanings as described above.];[1-11] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-10], wherein T is a nitrogen atom;[1-12] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-9] to [1-11], wherein U is a carbon atom;[1-13] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1], [1-3], [1-5] and [1-7] to [1-12], wherein Ring A is pyrazole,triazole (e.g., 1,2,3-triazole and 1,2,4-triazole), tetrazole, oxazole,isoxazole, imidazole, thiazole or isothiazole:[1-14] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to the preceding item [1-1],wherein the compound represented by the general formula (I-1) is thecompound represented by the general formula (III-1);

[wherein, all symbols represent the same meanings as described above.];[1-15] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-14], wherein L² in the general formula (I-1), generalformula (II-1) and general formula (III-1) (hereinafter, may beabbreviated as “the general formula (I-1) or the like”) is a bond orC1-3 alkylene group;[1-16] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-15], wherein L¹ in the general formula (I-1) or the like is—O—, —CONH—, —CO—, —CO₂—, —S—, —SO₂— or —SO—;[1-17] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-15], wherein L¹ in the general formula (I-1) or the like is—CONH— (provided that the left side of the group is bound to Ring B),—CO—, —CO₂—, —S—, —SO₂— or —SO—;[1-18] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-17]; wherein R¹ is a hydrogen atom, hydroxyl group, C1-4alkyl group or carboxy group;[1-19] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-17]; wherein R¹ is a hydrogen atom or C1-4 alkyl group;[1-20] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-19], wherein R^(2e) is a nitro group or NR^(2d)R^(2e);[1-21] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-20], wherein R³ is a hydrogen atom, halogen atom or hydroxylgroup:[1-22] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-21], wherein R^(2d) is a hydrogen atom or R^(FR);[1-23] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-22], wherein both of R^(4a) and R^(6a) are hydrogen atoms;[1-24] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-21], wherein R^(4a) is a hydrogen atom or R^(FR);[1-25] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-21] and (1-24], wherein both of R^(2d) and R^(6a) arehydrogen atoms;[1-26] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-21], wherein R^(6a) is a hydrogen atom or R^(FR);[1-27] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof according to any one of the preceding items[1-1] to [1-21] and [1-26], wherein both of R^(2d) and R^(4a) arehydrogen atoms;[1-28] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-27], wherein R^(FR) is —(CR^(Fb) ₂)_(q)OP(═O)(OR^(Fa))₂[wherein, all symbols represent the same meanings as described above.];[1-29] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to the preceding item [1-28],wherein —(CR^(fb) ₂)_(q)OP(═O)(OR^(Fa))₂ represented by R^(FR) is—CH₂OP(═O)(OH^(Fa))₂, —CH(CH₃)OP(═O)(OH)₂ or—CH₂OP(═O)(OH)(OCH₂OCO₂CH(CH₃)₂);[1-30] the pharmaceutically acceptable salt of the compound or thesolvate thereof, according to any one of the preceding items [1-1] to[1-28], wherein R^(FR) is —(CR^(Fb) ₂)_(q)OP(═O)(OR^(Fa))₂ and thepharmaceutically acceptable salt described in any one of the precedingitems [1-1] to [1-28] is an alkali metal salt (e.g., a lithium salt,sodium salt or potassium salt), alkaline earth metal salt (e.g., acalcium salt), magnesium salt, zinc salt, ammonium salt or organic aminesalt, formed together with the same group;[1-31] the pharmaceutically acceptable salt of the compound or thesolvate thereof, according to the preceding item [1-30], wherein theorganic amine salt is an aliphatic amine salt (e.g., methylamine salt,dimethylamine salt, cyclopentylamine salt, trimethylamine salt,triethylamine salt, dicyclohexylamine salt, monoethanolamine salt,diethanolamine salt, triethanolamine salt, procaine salt, megluminesalt, tris(hydroxymethyl)aminomethane salt or ethylenediamine salt,etc.), aralkylamine salt (e.g., benzylamine salt, phenethylamine salt,N,N-dibenzylethylenediamine salt or benetamine salt, etc.), heterocyclicaromatic amine salt (e.g., piperidine salt, pyridine salt, picolinesalt, quinoline salt or isoquinoline salt, etc.), quaternary ammoniumsalt (e.g., tetramethylammonium salt, tetraethylammonium salt,benzyltrimethylammonium salt, benzyltriethylammonium salt,benzyltributylammonium salt, methyltrioctylammonium salt ortetrabutylammonium salt, etc.), basic amino acid salt (e.g., argininesalt or lysine salt, etc.) or N-methyl-D-glucamine salt;[1-32] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to any one of the preceding items[1-1] to [1-31], p and pa are zero or 1;[1-33] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to the preceding item [1-1],wherein the compound represented by the general formula (I-1) is thecompound selected from the group consisting of:(1)4-(4-amino-2-fluoro-5-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[5,4-c]pyridin-3-amine,(2)4-(4-amino-2-fluoro-5-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,(3)4-(4-amino-3-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,(4)4-(4-amino-2-fluoro-5-(methylthio)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,(5)4-(4-amino-2-fluoro-5-(methoxy-d₃)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,(6)4-(4-amino-2-fluoro-5-(methylsulfonyl)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,(7)4-(4-amino-5-(ethylthio)-2-fluorophenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,(8)4-(4-amino-2-fluoro-5-(methylsulfanyl)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,(9)4-(4-amino-2-fluoro-3-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,(10) methyl2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate,(11)2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoicacid,(12)2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzamide,(13)4-(4-amino-2-fluoro-5-melhoxyphenyl)-7-(3-methyl-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,(14) methyl2-amino-5-(3-amino-7-(1-((phosphonooxy)methyl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate,(15)1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)ethan-1-one,(16)4-(4-amino-2-chloro-5-(methylthio)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,(17) ethyl2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate,(18)(4-(4-(5-acetyl-4-amino-2-fluorophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(19) ethyl2-amino-5-(3-amino-7-(1-((phosphonooxy)methyl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate,(20)2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluoro-N-methylbenzamide,(21)1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)propan-1-one,(22)2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-ethyl-4-fluorobenzamide,(23)1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)phenyl)ethan-1-one,(24) methyl2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)benzoate,(25)2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-propylbenzamide,(26)1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)butan-1-one,(27)2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluoro-N-propylbenzamide,(28)1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)phenyl)butan-1-one,(29) 2-hydroxyethyl2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate,(30)2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)benzamide,(31)2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-methylbenzamide,(32)(4-(3-amino-4-(4-amino-5-(ethylcarbamoyl)-2-fluorophenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(33)1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-hydroxyphenyl)ethan-1-one,(34)2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-ethylbenzamide,(35)1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)phenyl)propan-1-one,(36)2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-chloro-N-ethylbenzamide,(37)(4-(3-amino-4-(4-amino-2-fluoro-5-(methylthio)phenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(38)(4-(3-amino-4-(4-amino-2-fluoro-5-propionylphenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(39)(4-(4-(3-acetyl-4-aminophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(40)4-(2-fluoro-5-methoxy-4-nitrophenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,(41)(4-(3-amino-4-(4-amino-2-fluoro-5-(methylsulfonyl)phenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(42)(4-(3-amino-4-(4-amino-5-(ethylcarbamoyl)-2-chlorophenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(43)1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isothiazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)ethan-1-one,and(44)4-(4-amino-2-fluoro-5-(trifluoromethyl)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine;[1-34] the compound, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof, according to the preceding item [1-1],wherein the compound represented by the general formula (I-1) is thecompound selected from the group consisting of:(1) methyl2-amino-5-(3-amino-7-(1-((phosphonooxy)methyl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate,(2)(4-(4-(5-acetyl-4-amino-2-fluorophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(3) ethyl2-amino-5-(3-amino-7-(1-((phosphonooxy)methyl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate,(4)(4-(3-amino-4-(4-amino-5-(ethylcarbamoyl)-2-fluorophenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(5)(4-(3-amino-4-(4-amino-2-fluoro-5-(methylthio)phenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(6)(4-(3-amino-4-(4-amino-2-fluoro-5-propionylphenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(7)(4-(4-(3-acetyl-4-aminophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate,(8)(4-(3-amino-4-(4-amino-2-fluoro-5-(methylsulfonyl)phenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate, and(9)(4-(3-amino-4-(4-amino-5-(ethylcarbamoyl)-2-chlorophenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate;[1-35] the pharmaceutically acceptable salt of the compound or thesolvate thereof, according to any one of the preceding items [1-1] to[1-34], wherein the pharmaceutically acceptable salt of the compounddescribed in any one of the preceding items [1-1] to [1-34] is an alkalimetal salt (e.g., a lithium salt, sodium salt or potassium salt);[1-36] the solvate of the compound or the pharmaceutically acceptablesalt thereof, according to any one of the preceding items [1-1] to[1-35], wherein the solvate of the compound or the pharmaceuticallyacceptable salt thereof described in any one of the preceding items[1-1] to [1-35] is a hydrate;[2-1] a pharmaceutical composition containing the compound representedby the general formula (I), general formula (II) or general formula(III), an N-oxide thereof, a prodrug thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof and a pharmaceuticallyacceptable carrier;[2-2] a pharmaceutical composition containing the compound representedby the general formula (I-1), general formula (II-1) or general formula(III-1), an N-oxide thereof, a pharmaceutically acceptable salt thereofor a solvate thereof and a pharmaceutically acceptable carrier;[2-3] the pharmaceutical composition according to the preceding item[2-1] or [2-2], further containing one or more kinds of otheranti-cancer drugs as an active ingredient;[3-1] an agent for suppressing the progression of, suppressing therecurrence of and/or treating cancer or infectious disease, containingthe compound represented by the general formula (I), general formula(II) or general formula (III), an N-oxide thereof, a prodrug thereof, apharmaceutically acceptable salt thereof or a solvate thereof as anactive ingredient;[3-2] an agent for suppressing the progression of, suppressing therecurrence of and/or treating cancer or infectious disease, containingthe compound represented by the general formula (I-1), general formula(II-1) or general formula (III-1), an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof as anactive ingredient;[3-3] the agent according to the preceding item [3-1] or [3-2], whereinthe cancer is solid cancer or blood cancer,[3-4] the agent according to the preceding item [3-3], wherein the solidcancer is one or more cancers selected from malignant melanoma (e.g.,malignant melanoma in skin, oral mucosal epithelium or orbit, etc.),non-small cell lung cancer (e.g., squamous non-small cell lung cancerand non-squamous non-small cell lung cancer), small cell lung cancer,head and neck cancer (e.g., oral cancer, nasopharyngeal cancer,oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivarygland cancer and tongue cancer), renal cell cancer (e.g., clear cellrenal cell cancer), breast cancer, ovarian cancer (e.g., serous ovariancancer and ovarian clear cell adenocarcinoma), nasopharyngeal cancer,uterine cancer (e.g., cervical cancer and endometrial cancer), analcancer (e.g., anal canal cancer), colorectal cancer (e.g.,high-frequency microsatellite instability (hereinafter, abbreviated as“MS1-H”) and/or defective mismatch repair (hereinafter, abbreviated as“dMMR”) positive colorectal cancer), rectal cancer, colon cancer,hepatocellular carcinoma, esophageal cancer, gastric cancer,esophagogastric junction cancer, pancreatic cancer, urine urothelialcancer (e.g., bladder cancer, upper urinary tract cancer, ureteralcancer, renal pelvis cancer and urethral cancer), prostate cancer,fallopian tube cancer, primary peritoneal cancer, malignant pleuralmesothelioma, gallbladder cancer, bile duct cancer, biliary tractcancer, skin cancer (e.g., uveal melanoma and Merkel cell carcinoma),testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer,penile cancer, small intestine cancer, endocrine system cancer, thyroidcancer, parathyroid cancer, adrenal carcinoma, spinal tumor,neuroblastoma, medulloblastoma, ocular retinoblastoma, neuroendocrinetumor, brain tumor (e.g., glioma (e.g., glioblastoma and gliosarcoma)and meningioma) and squamous cell carcinoma;[3-5] the agent according to the preceding item [3-3], wherein the solidcancer is bone/soft tissue sarcoma (e.g., Ewing sarcoma pediatricrhabdomyosarcoma endometrial leiomyosarcoma, chondrosarcoma, lungsarcoma, osteosarcoma and congenital fibrosarcoma) or Kaposi's sarcoma;[3-6] the agent according to the preceding item [3-3], wherein the bloodcancer is one or more cancers selected from multiple myeloma, malignantlymphoma (e.g., non-Hodgkin lymphoma (e.g., follicular lymphoma,precursor B-cell lymphoblastic lymphoma, chronic B lymphocytic leukemia,nodal marginal zone B-cell lymphoma, diffuse large B-cell lymphoma, MALTlymphoma, splenic primary marginal zone B-cell lymphoma, hairy cellleukemia, primary mediastinal large B-cell lymphoma, Burkitt lymphoma,mantle cell lymphoma, mycosis fungoides, Sézary syndrome, chronic oracute lymphocytic leukemia, precursor T-cell lymphoblastic lymphoma,chronic T lymphocytic leukemia, large granular T cell leukemia, largegranular NK cell leukemia, peripheral T-cell lymphoma, extranodalNK/T-cell lymphoma, adult T-cell leukemia, angiocentric lymphoma,intestinal T-cell lymphoma, Hodgkin-like/Hodgkin-related anaplasticlarge cell lymphoma, B-cell lymphoblastic leukemia, T-cell lymphoblasticleukemia and lymphoplasmacytoid lymphoma) and Hodgkin lymphoma (e.g.,classic Hodgkin lymphoma and nodular lymphoid predominant Hodgkinlymphoma)), leukemia (e.g., acute myelogenous leukemia and chronicmyelogenous leukemia), central nervous system malignant lymphoma,myelodysplastic syndromes and myeloproliferative syndromes;[3-7] the agent according to the preceding item [3-1] or [3-2], whereintire cancer is pediatric cancer or unknown primary cancer;[3-8] the agent according to any one of the preceding items [3-1] to[3-7], wherein the cancer is die cancer on which the therapeutic effectsof other anti-cancer drugs are insufficient or not sufficient;[3-9] the agent according to any one of the preceding items [3-1] to[3-8], wherein the cancer is worsened after treatment with otheranti-cancer drugs;[3-10] the agent according to any one of the preceding items [3-1] to[3-7], wherein a patient with cancer has not been treated with otheranti-cancer drugs;[3-11] the agent according to any one of the preceding items [3-1] to[3-10], which is prescribed in postoperative adjuvant therapy orpreoperative adjuvant therapy;[3-12] the agent according to any one of the preceding items [3-1] to[3-11], wherein the cancer is incurable or unresectable, metastatic,recurrent, refractory and/or distant metastatic;[3-13] the agent according to any one of the preceding items [3-1] to[3-12], wherein the ratio of PD-L1-expressing tumor cells among tumorcells in tumor tissue (hereinafter, abbreviated as “TPS”) or thenumerical value obtained by dividing the number of PD-L1 positive cells(tumor cells, lymphocytes and macrophages) by the total number of tumorcells and multiplying by 100 (hereinafter, abbreviated as “CPS”) is 50%or more, 25% or more, 10% or more, 5% or more, or 1% or more;[3-14] the agent according to any one of the preceding items [3-1] to[3-12], wherein TPS is less than 50%, less than 25%, less than 10%, lessthan 5% or less than 1%;[3-15] the agent according to any one of the preceding items [3-1] to[3-14], wherein the cancer has MSI-H and/or dMMR;[3-16] the agent according to any one of the preceding items [3-1] to[3-14], wherein the cancer does not have MSI-H and/or dMMR, or has lowfrequency microsatellite instability (hereinafter, abbreviated as“MSI-L”);[3-17] the agent according to any one of the preceding items [3-4] to[3-16], wherein malignant melanoma or non-small cell lung cancer is BRAFV600E mutation-positive;[3-18] the agent according to any one of the preceding items [3-4] to[3-16], wherein malignant melanoma or non-small cell lung cancer is BRAFV600E wild-type;[3-19] the agent according to any one of the preceding items [3-4] to[3-18], wherein non-small cell lung cancer is EGFR gene mutationpositive and/or ALK fusion gene positive;[3-20] the agent according to any one of the preceding items [3-4] to[3-18], wherein non-small cell lung cancer is EGFR gene mutationnegative and/or ALK fusion gene negative;[3-21] the agent according to any one of the preceding items [3-1] to[3-20], wherein tumor mutation burden (hereinafter, abbreviated as“TMB”.) of the cancer is high frequency (10 mutations or more per 10⁶bases);[3-22] the agent according to any one of the preceding items [3-1] to[3-20], wherein TMB of the cancer is low frequency (less than 10mutations per 10⁶ bases);[3-23] the agent according to any one of the preceding items [3-1] to[3-22], which is characterized by further being administered incombination with one or more kinds of other anti-cancer drugs;[4-1] the agent according to the preceding item [3-1] or [3-2], whereinthe infectious disease is a condition caused by viral infection,parasitic infection, bacterial infection or fungal infection;[4-2] the agent according to the preceding item [4-1], wherein the virusinfection disease is the infection disease caused by adenovirus,arenavirus, bunyavirus, calicivirus, coronavirus, filovirus,hepadnavirus, herpesvirus, orthomyxovirus, papovavirus, paramyxovirus,parvovirus, picomavirus, poxvirus, reovirus, retrovirus, rhabdovirus,togavirus, papillomavirus (e.g., human papillomavirus (HPV)), humanimmunodeficiency virus (HIV), poliovirus, hepatitis virus (e.g.,hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus(HCV), hepatitis D virus (HDV) and hepatitis E virus (HEV)), smallpoxvirus (e.g., variola major and variola minor), vaccinia virus, influenzavirus, rhinovirus, dengue virus, equine encephalitis virus, rubellavirus, yellow fever virus, Norwalk virus, human T-cell leukemia virus(HTLV-1), hairy cell leukemia virus (HTLV-II), California encephalitisvirus, hanta virus (hemorrhagic fever), rabies virus, Ebola virus,Marburg virus, measles virus, mumps virus, respiratory syncytial virus(RSV), herpes simplex type I (oral herpes), herpes simplex type 2(genital herpes), herpes zoster (varicella-zoster virus),cytomegalovirus (CMV). Epstein-Barr virus (EBV), flavivirus,foot-and-mouth disease virus, Chikungunya vims, Lassa virus, arenavirusor oncovirus;[5-1] a method for suppressing the progression of, suppressing therecurrence of and/or treating cancer or infectious disease, comprisingadministering an effective dose of the compound represented by thegeneral formula (I), an N-oxide thereof, a prodrug thereof, apharmaceutically acceptable salt thereof or a solvate thereof to apatient in need thereof;[5-2] a method for suppressing the progression of, suppressing therecurrence of and/or treating cancer or infectious disease, comprisingadministering an effective dose of the compound represented by thegeneral formula (I-1), an N-oxide thereof, a pharmaceutically acceptablesalt thereof or a solvate thereof to a patient in need thereof;[6-1] a compound represented by the general formula (I), an N-oxidethereof, a prodrug thereof, a pharmaceutically acceptable salt thereofor a solvate thereof for use in suppressing the progression of,suppressing the recurrence of and/or treating cancer or infectiousdisease;[6-2] a compound represented by the general formula (I-1), an N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvate thereoffor use in suppressing the progression of, suppressing the recurrence ofand/or treating cancer or infectious disease;[7-1] use of a compound represented by the general formula (I), anN-oxide thereof, a prodrug thereof, a pharmaceutically acceptable saltthereof or a solvate thereof in manufacturing a drug for suppressing theprogression of, suppressing the recurrence of and/or treating cancer orinfectious disease;[7-2] use of a compound represented by the general formula (I-1), anN-oxide thereof, a pharmaceutically acceptable salt thereof or a solvatethereof in manufacturing a drug for suppressing the progression of,suppressing the recurrence of and/or treating cancer or infectiousdisease;[8-1] the pharmaceutical composition according to the preceding item[2-3] or the agent according to any one of the preceding items [3-8] to[3-10] and [3-23], wherein the other anti-cancer drugs described in thepreceding item [2-3], [3-8] to [3-10] or [3-23] are one or more kinds ofagents selected from an alkylating agent, platinum preparation,antimetabolite (e.g., antifolate, pyridine metabolism inhibitor andpurine metabolism inhibitor), ribonucleotide reductase inhibitor,nucleotide analog, topoisomerase inhibitor, microtubule polymerizationinhibitor, microtubule depolymerization inhibitor, antitumor antibiotic,cytokine preparation and anti-hormonal drug;[8-2] the pharmaceutical composition according to the preceding item[2-3] or the agent according to any one of the preceding items [3-8] to[3-10] and [3-23], wherein the other anti-cancer drug described in thepreceding item [2-3], [3-8] to [3-10] or [3-23] is a molecular targetingdrug;[8-3] the pharmaceutical composition according to the preceding item[8-2] or the agent according to the preceding item [8-2], wherein themolecular targeting drug is one or more kinds of agents selected from anALK inhibitor, BCR-ABL inhibitor, EGFR inhibitor, B-Raf inhibitor, VEGFRinhibitor, FGFR inhibitor, c-Met inhibitor, Ax1 inhibitor, Mckinhibitor, CDK inhibitor, Btk inhibitor, PI3K-δ/γ inhibitor, JAK-1/2inhibitor, TGFbR1 inhibitor, Cancer cell sternness kinase inhibitor,Syk/FLT3 dual inhibitor, ATR inhibitor. Wee 1 kinase Inhibitor,multi-tyrosine kinase inhibitor, mTOR inhibitor, HDAC inhibitor, PARPinhibitor, aromatase inhibitor, EZH2 inhibitor, galectin-3 inhibitor,STAT3 inhibitor, DNMT inhibitor, SMO inhibitor, Hsp90 inhibitor,γ-tubulin specific inhibitor, HIF2α inhibitor, glutaminase inhibitor, E3ligase inhibitor, Nrf2 activator, arginase inhibitor, cell cycleinhibitor, IAP antagonist, anti-Her2 antibody, anti-EGFR antibody,anti-VEGF antibody, anti-VEGFR2 antibody, anti-CD20 antibody, anti-CD30antibody, anti-CD38 antibody, anti-DR5 antibody, anti-CA125 antibody,anti-DLL4 antibody, anti-fucosyl GM1 antibody, anti-gpNMB antibody,anti-Mesothelin antibody, anti-MMP9 antibody, anti-GD2 antibody,anti-c-Met antibody, anti-FOLR1 antibody, anti-Ang2-VEGF bispecificantibody, anti-CD30-CD16A bispecific antibody, anti-CD79b antibody,anti-FAP antibody/IL-2 fusion protein, anti-CEA antibody/IL-2 fusionprotein, anti-CEA-CD3 bispecific antibody, anti-DLL3 antibody,anti-CD3-CD19 bispecific antibody and anti-CD20-CD3 bispecific antibody;[8-4] the pharmaceutical composition according to the preceding item[2-3] or the agent according to any one of the preceding items [3-8] to[3-10] and [3-23], wherein the other anti-cancer drug described in thepreceding item [2-3], [3-8] to [3-10] or [3-23] is a cancerimmunotherapeutic drug;18-5) the pharmaceutical composition according to the preceding item[8-4] or the agent according to the preceding item [8-4], wherein thecancer immunotherapeutic drug is one or more kinds of agents selectedfrom an anti-PD-1 antibody, anti-PD-L1 antibody, PD-1 antagonist,PD-L1/VISTA antagonist, PD-L1/TIM3 antagonist, anti-PD-L2 antibody,PD-L1 fusion protein. PD-L2 fusion protein, anti-CTLA-4 antibody,anti-LAG-3 antibody, LAG-3 fusion protein, anti-Tim3 antibody, anti-KIRantibody, anti-BTLA antibody, anti-TIGIT antibody, anti-VISTA antibody,anti-CD137 antibody, anti-CSF-1R antibody/CSF-1R inhibitor, anti-OX40antibody, anti-HVEM antibody, anti-CD27 antibody, anti-GITR antibody,anti-CD28 antibody, anti-CCR4 antibody, anti-B7-H3 antibody, anti-ICOSagonistic antibody, anti-CD4 antibody, anti-DEC-205 antibody/NY-ESO-1fusion protein, anti-SLAMF7 antibody, anti-CD73 antibody, anti-CD122antibody, anti-CD40 agonistic antibody, IDO inhibitor, TLR agonist.Adenosine A2A receptor antagonist, anti-NKG2A antibody, anti-CSF-1antibody, immunopotentiator, IL-15 super agonist, soluble LAG3, CD47antagonist and IL-12 antagonist;[8-6] the pharmaceutical composition according to the preceding item[8-5] or the agent according to the preceding item [8-5], wherein theanti-PD-1 antibody is the antibody selected from Nivolumab, Cemiplimab,Pembrolizumab, Spartalizumab, Tislelizumab, AMP-514, Dostarlimab,Toripalimab, Camrelizumab, Genolimzumab. Sintilimab, STI-A1110, ENUM388D4, ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003, HLX10, BAT-1306,AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034,HX008, ABBV181, BCD-100, ISU106, PF-06801591, CX-188, JNJ-63723283 andAB122; [8-7] the pharmaceutical composition according to the precedingitem [8-5] or the agent according to the preceding item [8-5], whereinthe anti-PD-L1 antibody is the antibody selected from Atezolizumab,Avelumab, Durvalumab, BMS-936559, STI-1014, KN035, LY3300054, HLX20,SHR-1316, CS1001. MSB2311, BGB-A333, KL-A167, CK-301, AK106. AK104,ZKAB001, FAZ053, CBT-502, JS003 and CX-072;[9-1] a STING agonistic agent containing the compound represented by thegeneral formula (I), general formula (II) or general formula (III), anN-oxide thereof, a prodrug thereof, a pharmaceutically acceptable saltthereof or a solvate thereof as an active ingredient;[9-2] a STING agonistic agent containing the compound represented by thegeneral formula (I-1), general formula (II-1) or general formula(III-1), an N-oxide thereof, a pharmaceutically acceptable salt thereofor a solvate thereof as an active ingredient;[10-1] an IFN-β production inducer containing the compound representedby the general formula (I), general formula (II) or general formula(III), an N-oxide thereof, a prodrug thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof as an active ingredient;and[10-2] an IFN-β production inducer containing the compound representedby the general formula (I-1), general formula (II-1) or general formula(III-1), an N-oxide thereof, a pharmaceutically acceptable salt thereofor a solvate thereof as an active ingredient.[Advantage Effects of Invention]

Since the compound of the present invention has the agonistic activityto STING, it can be used as an active ingredient of the agent forsuppressing the progression of, suppressing the recurrence of and/ortreating cancer or infectious disease.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 It shows the antitumor activity of the compound of the presentinvention (the compound shown in Example 1) in a subcutaneous tumormodel bearing mouse colon cancer cell line MC38. A vehicle and thecompound of the present invention (n=6) were administered 7 days afterthe MC38 transplantation, respectively, and the change in tumor volumewas continuously measured until 26 days after the transplantation.

FIG. 2 It shows the antitumor activity of the compound of the presentinvention (each compound shown in Examples 10, 10 (1) and 10 (2)) in thesubcutaneous tumor model bearing mouse colon cancer cell line MC38. Avehicle and the compounds of the present invention (n=8) wereadministered 7 days after the MC38 transplantation, respectively, andthe change in tumor volume was continuously measured until 28 days afterthe transplantation.

FIG. 3 It shows the antitumor activity of the compounds of the presentinvention (each compound shown in Examples 10 (3) to 10 (6)) in thesubcutaneous tumor model bearing mouse colon cancer cell line MC38. Avehicle and the compounds of the present invention (n=6) wereadministered 8 days after the MC38 transplantation, respectively, andthe change in tumor volume was continuously measured until 30 days afterthe transplantation.

DESCRIPTION OF EMBODIMENTS

In the present specification, examples of the “halogen atom” include afluorine atom, chlorine atom, bromine atom and iodine atom.

In the present specification, examples of the “C1-4 alkyl group” includea methyl group, ethyl group, n-propyl group, isopropyl group, n-butylgroup, isobutyl group, sec-butyl group and tert-butyl group.

In the present specification, examples of the “C1-5 alkyl group” includea methyl group, ethyl group, M-propyl group, isopropyl group, n-butylgroup, isobutyl group, sec-butyl group, tert-butyl group, pentyl group,isopentyl group and 2,3-dimethylpropyl group.

In the present specification, the “C1-3 alkylene group” is a methylenegroup, ethylene group or propylene group.

In the present specification, examples of the “C1-4 alkoxy group”include a methoxy group, ethoxy group, n-propoxy group, isopropoxygroup, n-butoxy group, isobutoxy group, sec-butoxy group and tert-butoxygroup.

In the present specification, examples of the “C1-4 haloalkyl group”include a fluoromethyl group, chloromethyl group, bromomethyl group,iodomethyl group, difluoromethyl group, trifluoromethyl group,1-fluoroethyl group, 2-fluoroethyl group, 2-chloroethyl group,pentafluoroethyl group, 1-fluoropropyl group, 2-chloropropyl group,3-fluoropropyl group, 3-chloropropyl group, 4,4,4-trifluorobutyl groupand 4-bromobutyl and the like.

In the present specification, examples of the “C1-4 haloalkoxy group”include a trifluoromethoxy group, trichloromethoxy group, chloromethoxygroup, bromomethoxy group, fluoromethoxy group, iodomethoxy group,difluoromethoxy group, dibromomethoxy group, 2-chloroethoxy group,2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, 3-bromopropoxygroup, 3-chloropropoxy group, 2,3-dichloropropoxy group and the like.

In the present specification, examples of the “C3-6 cycloalkyl group”include a cyclopropyl group, cyclobutyl group, cyclopentyl group andcyclohexyl group.

In the present specification, examples of the “C3-7 cycloalkyl group”include a cyclopropyl group, cyclobutyl group, cyclopentyl group,cyclohexyl group and cycloheptyl group.

In the present specification, examples of the “C3-7 cycloalkylene group”include a cyclopropylene group, cyclobutylene group, cyclopentylenegroup, cyclohexylene group and cycloheptylene group.

In the present specification, examples of the “C1-4 alkoxycarbonylgroup” include a methoxycarbonyl group, ethoxycarbonyl group,n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonylgroup, isobutoxycarbonyl group, sec-butoxycarbonyl group, andten-butoxycarbonyl group.

In the present specification, examples of the “C5-6 monocycliccarbocycle” include a cyclopentane, cyclohexane, cyclopentene,cyclohexene, cyclopentadiene, cyclohexadiene, benzene and the like.

In the present specification, examples of the “5 to 7-memberedmonocycle” include a cyclopentane, cyclohexane, cyclopentene,cyclohexene, cyclopentadiene, cyclohexadiene, benzene, cycloheptane,cycloheptene, cycloheptadiene, pyrrole, oxazole, isoxazole, thiazole,isothiazole, pyrroline, pyrrolidine, dihydrooxazole, tetrahydrooxazole,dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole,tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole,imidazole, pyrazole, furazan, oxadiazole, thiadiazole, imidazoline,imidazolidine, pyrazoline, pyrazolidine, dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole,dihydrothiadiazole, tetrahydrothiadiazole, triazole, triazoline,triazolidine, tetrazole, tetrazoline, tetrazolidine, furan,dihydrofuran, tetrahydrofuran, oxolane, dioxolane, thiophene,dihydrothiophene, tetrahydrothiophene, dithiolane, pyridine, oxazine,thiazine, dihydropyridine, tetrahydropyridine, piperidine,dihydrooxazine, tetrahydrooxazine, dihydrothiazine, tetrahydrothiazine,morpholine, thiomorpholine, pyrazine, pyrimidine, pyridazine,oxadiazine, thiadiazine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazine,tetrahydrothiadiazine, pyran, dihydropyran, tetrahydropyran, oxothiane,dioxothiane, oxathiane, dioxane, thiopyran, dihydrothiopyran,tetrahydrothiopyran, dithiane, azepine, diazepine, oxepin, thiepine,oxazepine, oxadiazepine, thiazepine, thiadiazepine, dihydroazepine,tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxepin, tetrahydrooxepin,perhydrooxepin, dihydrothiepine, tetrahydrothiepine, perhydrothiepine,dihydrooxazepine, tetrahydrooxazepine, perhydroxazepine,dihydroxadiazepine, tetrahydroxadiazepine, perhydroxadiazepine,dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine andthe like.

In the present specification, examples of the “8 to 10-membered bicycle”include a pentalene, perhydropentalene, indene, perhydroindene, indane,azulene, perhydroazulene, naphthalene, dihydronaphthalene,tetrahydronaphthalene, perhydronaphthalene, thienopyrazole,thienoimidazole, pyrazolothiazole, indole, isoindole, indolizine,benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole,purine, benzoxazole, benzothiazole, benzimidazole, imidazopyridine,benzofurazan, benzothiadiazole, benzotriazole, indoline, isoindoline,dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran,perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene,dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole,perhydroindazole, dihydrobenzoxazole, perhydrobenzoxazole,dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole,perhydrobenzimidazole, dioxoindane, benzodithiolane, dithianaphthalene,quinoline, isoquinoline, quinolidine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, chromene,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,benzooxathiane, dihydrobenzoxazine, dihydrobenzothiazine,pyrazinomorpholine, benzodioxane, chroman, benzodithiane and the like.

In the present specification, examples of the “5 to 6-memberedmonocyclic heterocycle containing 1 to 4 heteroatoms selected from anoxygen atom, nitrogen atom and sulfur atom” include a pyrrole, oxazole,isoxazole, thiazole, isothiazole, pyrroline, pyrrolidine,dihydrooxazole, tetrahydrooxazole, dihydroisoxazole,tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole,dihydroisothiazole, tetrahydroisothiazole, imidazole, pyrazole, furazan,oxadiazole, thiadiazole, imidazoline, imidazolidine, pyrazoline,pyrazolidine, dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole, dihydrothiadiazole, tetrahydrothiadiazole,triazole, triazoline, triazolidine, tetrazole, tetrazoline,tetrazolidine, furan, dihydrofuran, tetrahydrofuran, oxolane, dioxolane,thiophene, dihydrothiophene, tetrahydrothiophene, dithiolane, pyridine,oxazine, thiazine, dihydropyridine, tetrahydropyridine, piperidine,dihydrooxazine, tetrahydrooxazine, dihydrothiazine, tetrahydrothiazine,morpholine, thiomorpholine, pyrazine, pyrimidine, pyridazine,oxadiazine, thiadiazine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazine,tetrahydrothiadiazine, pyran, dihydropyran, tetrahydropyran, oxothiane,dioxothiane, oxathiane, dioxane, thiopyran, dihydrothiopyran,tetrahydrothiopyran, dithiane and the like.

In the present specification, examples of the “5 to 6-memberedmonocyclic aromatic heterocycle containing 1 to 4 heteroatoms selectedfrom an oxygen atom, nitrogen atom and sulfur atom” include a pyrrole,imidazole, triazole, tetrazole, pyrazole, furan, thiophene, oxazole,isoxazole, thiazole, isothiazole, furazan, oxadiazole, thiadiazole,pyridine, pyrazine, pyrimidine, pyridazine and the like.

In the present specification, examples of the “5 to 6-memberedmonocyclic aromatic nitrogen-containing heterocycle containing 1 to 4nitrogen atoms and without any other heteroatoms” include a pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine and the like.

In the present specification, examples of the “3 to 7-memberedmonocyclic non-aromatic heterocycle” include an oxirane, aziridine,thiirane, azetidine, oxetane, thietane, pyrroline, pyrrolidine,imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline,tetrazolidine, pyrazoline, pyrazolidine, dihydrofuran, tetrahydrofuran,dihydrothiophene, tetrahydrothiophene, dihydrooxazole,tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole,dihydrothiazole, tetrahydrothiazole, dihydroisothiazole,tetrahydroisothiazole, dihydrofurazan, tetrahydrofurazan,dihydrooxadiazole, tetrahydrooxadiazole, dihydrothiadiazole,tetrahydrothiadiazole, oxolane, dioxolane, dithiolane, pyran, thiopyran,oxazine, oxadiazine, thiazine, thiadiazine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydropyran, tetrahydropyran, dihydrothiopyran, tetrahydrothiopyran,dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine,oxothiane, dioxothiane, oxathiane, dioxane, dithiane, azepine,diazepine, oxepin, thiepine, oxazepine, oxadiazepine, thiazepine,thiadiazepine, dihydroazepine, tetrahydroazepine, perhydroazepine,dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxepin,tetrahydrooxepin, perhydrooxepin, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine and the like.

In the specification of the present invention, examples of the “freeradical group producing a compound represented by the general formula(I), N-oxide thereof, pharmaceutically acceptable salt thereof orsolvate thereof, as a result of decomposition in vivo” include the groupdefined as R^(FR).

Ring A in the general formula (I), (I-1), (II) or (II-1) of the presentinvention is preferably a 5 to 6-membered monocyclic aromaticheterocycle containing 1 to 4 heteroatoms selected from an oxygen atom,nitrogen atom and sulfur atom, more preferably pyrazole, triazole (e.g.,1,2,3-triazole and 1,2,4-triazole), tetrazole, oxazole, isoxazole,imidazole, thiazole or isothiazole, and furthermore preferably,pyrazole, while Ring B of the general formula (I) or (I-1) of thepresent invention is preferably (i) a C5-6 monocyclic carbocycle or (ii)a 5 to 6-membered monocyclic heterocycle containing 1 to 4 heteroatomsselected from an oxygen atom, nitrogen atom and sulfur atom, and morepreferably benzene.

Further, Z in the general formula (I) or (I-1) of the present inventionis preferably an oxygen atom, Y is preferably —CH═ and X is preferably anitrogen atom,

L² in the general formula (I) or the like, the formula (Ib), the generalformula (I-1) or the like or the formula (Ib-1) of the present inventionis preferably a bond or C1-3 alkylene group, and more preferably, abond, and L¹ is preferably —O—, —CONH—, —CO—, —CO₂—, —S—, —SO₂— or —SO—,and more preferably —CONH— (provided that the left side of the group isattached bond to the Ring B), —CO—, —CO₂—, —S—, —SO₂— or —SO—, R¹ ispreferably a hydrogen atom, hydroxyl group, C1-4 alkyl group or carboxygroup, more preferably a hydrogen atom or C1-4 alkyl group, andfurthermore preferably a hydrogen atom, methyl group, ethyl group orw-propyl group, R² and R^(2c) are preferably a nitro group andNR^(2a)R^(2b) and NR^(2d)R^(2e), respectively, more preferably an aminogroup, and R³ is preferably a hydrogen atom, halogen atom or hydroxylgroup, and more preferably a halogen atom.

In the general formula (I) or the like, the formula (Ib), the generalformula (I-1) or the like or the formula (Ib-1) of the presentinvention, m is preferably 1 and p and pa are preferably zero or 1, andmore preferably zero. In the formula (Ib) or (Ib-1) or the generalformula (II), (II-1), (III) or (III-1) of the present invention, n ispreferably 2 or 1.

R^(2a), R⁴ and R⁶ in the general formula (I) or the like of the presentinvention are preferably hydrogen atoms, and R^(2d), R^(4a) and R^(6a)in the general formula (I-1) or the like are preferably hydrogen atomsor phosphonooxyalkyl group, and the phosphonooxyalkyl group ispreferably —CH₂OP(═O)(OH)₂, —CHCH₃OP(O)(OH)₂ or—CH₂OP(═O)(OH)(OCH₂OCO₂CH(CH₃)₂), and more preferably —CH₂OP(═O)(OH)₂.However, two or more of R^(2d), R^(4a) and R^(6a) do not represent thephosphonooxyalkyl groups, simultaneously.

W in the formula (Ib), formula (Ib-1), general formula (II), generalformula (II-1), general formula (III) or general formula (III-1) of thepresent invention is preferably and V is preferably —CH═.

U in the formula (Ib), formula (Ib-1), general formula (II) or generalformula (II-1) of the present invention is preferably a carbon atom.

T in the general formula (I), (I-1), (II) or (II-1) of the presentinvention is preferably a nitrogen atom.

The compound represented by the general formula (I) of the presentinvention, N-oxide thereof, prodrug thereof, pharmaceutically acceptablesalt thereof or solvate thereof is preferably a compound represented bythe general formula (II), N-oxide thereof, prodrug thereof,pharmaceutically acceptable salt thereof, or solvate thereof, morepreferably a compound represented by the general formula (III), N-oxidethereof, prodrug thereof, pharmaceutically acceptable salt thereof orsolvate thereof.

Furthermore, the compounds represented by the general formula (I),N-oxides thereof, prodrugs thereof, pharmaceutically acceptable saltsthereof, or solvates thereof are preferable, for example, the compounds(1) to (35) described in the preceding item [26], N-oxides thereof,prodrugs thereof, pharmaceutically acceptable salts thereof, or solvatesthereof.

In addition, the compound represented by the general formula (I-1) ofthe present invention, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof is preferably the compound represented by thegeneral formula (II-1), N-oxide thereof, pharmaceutically acceptablesalt thereof or solvate thereof, more preferably a compound representedby the general formula (III-1), N-oxide thereof, pharmaceuticallyacceptable salt thereof or solvate thereof.

Furthermore, the compounds represented by the general formula (I-1),N-oxides thereof pharmaceutically acceptable salts thereof, or solvatesthereof are preferably, for example, the compounds of (1) to (44)described in the preceding item [1-33], N-oxides thereof,pharmaceutically acceptable salts thereof, or solvates thereof. Further,the solvates of the compounds described in the preceding item [1-33] arepreferably hydrates of the compounds of (1) to (44) described in thepreceding item [1-33] or pharmaceutically acceptable salts thereof(e.g., alkali metal salts (e.g., lithium salt, sodium salt and potassiumsalt, etc.)).

[Isomers]

Unless otherwise specified in the present invention, examples of isomersinclude all of them. For example, alkyl groups include straight andbranched ones. Further, geometric isomers (E-form, Z-form, cis-form,trans-form) in double bonds, rings and condensed rings, optical isomersdue to the presence of an asymmetric carbon atom and the like (R,S-form, α, β configuration, enantiomers, diastereomers), opticallyactive substances having optical activity (O, L, d, l isomers), polarsubstances (high polar substances, low polar substances) bychromatographic separation, equilibrium compounds, rotamers, and thesemixtures in any proportion, racemic mixtures, are all included in thepresent invention. In addition, the present invention also includes allisomers due to tautomers.

Further, the optical isomers in the present invention are not limited to100% pure ones, and may contain less than 50% other optical isomers.

In the present invention, unless otherwise specified, as being apparentto those skilled in the art, the symbols:

represents that it is connected to the other side of the paper (that is,a arrangement),

represents that it is connected to the front side of the paper (that is,f) arrangement),

represents that it is α-configuration, β-configuration or a mixturethereof in any ratio, and

represents a single bond or double bond.

[N-Oxide Forms]

The compound represented by the general formula (I) or the like or thegeneral formula (I-1) or the like can be converted into an N-oxide formthereof by a known method. The N-oxide form means a compound representedby the general formula (I) or the like or the general formula (I-1) orthe like in which the nitrogen atom is oxidized. Further, these N-oxideforms can become prodrugs thereof, pharmaceutically acceptable saltsthereof or solvates thereof, as described in the item [Prodrugs] below,item [Salts] below and item [Solvates] below.

[Prodrugs]

The compound represented by the general formula (I) or the like orN-oxide thereof can be converted into a prodrug thereof by a knownmethod. The prodrug is a compound which is converted into, for example,the compound represented by the general formula (I) or the like orN-oxide form thereof by a reaction with enzymes or gastric acid or thelike in vivo. For example, the compound represented by the generalformula (I-1) or the like or N-oxide thereof in which any one of R^(2d),R^(4a) and R^(6a) is the preceding R^(FR) can be administered as aprodrug of the compound represented by the general formula (I) or thelike or N-oxide form thereof, and the prodrugs are preferably, forexample, the compounds in items (14), (18), (19), (32), (37) to (39),(41) and (42) described in the preceding item [1-33]. The prodrugs ofthe compounds represented by the general formula (I) or N-oxide formthereof may be changed to the corresponding compound represented by thegeneral formula (I) or the like or N-oxide thereof under physiologicalconditions as described in Hirokawa Shoten, 1990, “Development ofPharmaceuticals”, Volume 7, “Molecular Design,” pages 163-198.

Examples of other prodrugs of the compound represented by the generalformula (I) or the like or N-oxide form thereof include, in the casethat the compound represented by the general formula (I) or the like orN-oxide form thereof has a 5 to 6-membered monocyclic aromaticnitrogen-containing heterocycle containing 1 to 4 nitrogen atoms and noother heteroatom, the compounds in which a nitrogen atom on thenitrogen-containing heterocycle is acylated, alkylated or phosphorylated(e.g., a compound in which the nitrogen atom on the nitrogen-containingheterocycle in the compound represented by the general formula (I) orthe like is eicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,acetoxymethylated or tert-butylated etc.), in the case that the compoundrepresented by the general formula (I) or the like has an amino group,the compounds in which the amino group is acylated, alkylated orphosphorylated (e.g., the compound in which the amino group in thecompound represented by the general formula (I) or the like iseicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,acetoxymethylated or tert-butylated, etc.), in the case that thecompound represented by the general formula (I) or the like has ahydroxyl group, the compounds in which the hydroxyl group is acylatedalkylated, phosphorylated or borated (e.g., the compound in which thehydroxyl group in the compound represented by the general formula (I) orthe like is acetylated palmitoylated, propanoylated pivaloylated,succinylated, fumarylated alanylated or dimethylaminomethylcarbonylated,etc.), and in the case that the compound represented by the generalformula (I) or the like has a carboxy group, the compounds in which thecarboxy group is esterified or amidated (e.g., the compound in which thecarboxy group of the compound represented by the general formula (I) orthe like is ethylesterified, phenylesterified, carboxymethylesterified,dimethylaminomethylesterified, pivaloyloxymethylesterified,1-{(ethoxycarbonyl)oxy}ethylesterified, phthalidylesterified(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified1-{[(cyclohexyloxy)carbonyl]oxy}ethylesterified or methylamidated etc.)and the like. These compounds per se can be produced by a method known.In addition, the prodrug of the compound represented by the generalformula (I) or the like or N-oxide form thereof may become apharmaceutically acceptable salt thereof or solvate thereof, asdescribed in the item [Salts] below and item (Solvate] below.

[Salts]

The compound represented by the general formula (I) or the like, N-oxidethereof or prodrug thereof and the compound represented by the generalformula (I-1) or the like or N-oxide thereof can be converted into thecorresponding acceptable salt by a known method.

Herein, examples of the pharmaceutically acceptable salts include analkali metal salt (e.g., lithium salt, sodium salt and potassium salt,etc.), alkaline earth metal salt (e.g., calcium salt, magnesium salt andbarium salt, etc.), ammonium salt, organic amine salt (e.g., aliphaticamine salt (e.g., methylamine salt, dimethylamine salt, cyclopentylaminesalt, trimethylamine salt, triethylamine salt, dicyclohexylamine salt,monoethanolamine salt, diethanolamine salt, triethanolamine salt,procaine salt, meglumine salt, tris(hydroxymethyl)aminomethane salt, andethylenediamine salt, etc.), aralkylamine salt (e.g., benzylamine salt,phenethylamine salt, N,N-dibenzylethylenediamine salt and benetaminesalt, etc.), heterocyclic aromatic amine salt (e.g., piperidine salt,pyridine salt, picoline salt, quinoline salt and isoquinoline salt,etc.), quaternary ammonium salt (e.g., tetramethylammonium salt,tetraethylammonium salt, benzyltrimethylammonium salt,benzyltriethylammonium salt, benzyltributylammonium salt,methyltrioctylammonium salt and tetrabutylammonium salt, etc.), basicamino acid salt (e.g., arginine salt, lysine salt, etc.) andW-methyl-D-glucamine salts, etc.), acid adduct salt (e.g., inorganicacid salt (e.g. hydrochloride salt, hydrobromide salt, hydroiodide salt,sulphate, phosphate and nitrate etc.) and organic acid salt (e.g.,acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate,maleate, benzoate, citrate, methanesulfonate, ethanesulfonate,benzenesulfonate, toluenesulfonate, isethionate, glucuronate andgluconate, etc.), etc.) and the like. The pharmaceutically acceptablesalt is preferably water-soluble.

In particular, among the compounds represented by the general formula(I-1) or the like in which any one of R^(2d), R^(4a) and R^(6a) is theabove-mentioned phosphonooxyalkyl group, 25 examples of ones which forma salt along with the same group include the above-mentioned alkalimetal salt, the above-mentioned alkaline earth metal salt, magnesiumsalt, zinc salt, ammonium salt, organic amine salt and the like, andamong these salts, the alkali metal salt is preferably a sodium salt andpotassium salt, the alkaline earth metal salt is preferably a calciumsalt, and tire organic amine salt is preferably a basic amino acid salt(e.g., arginine salt (e.g., L-30 arginine salt), lysine salt (e.g.,L-lysine salt), etc.), meglumine salt, tris(hydroxymethyl)aminomethanesalt and the like.

[Solvates]

The compound represented by the general formula (I) or the like, N-oxidethereof, prodrug thereof or pharmaceutically acceptable salt thereof andthe compound represented by the general formula (I-1) or the like,N-oxide thereof or pharmaceutically acceptable salt thereof can also beconverted into a solvate by a known method. The solvate is preferablylow toxicity and water soluble. Examples of suitable solvates include asolvate with a solvent such as water and alcohols (e.g., ethanol etc.).Herein, a hydrate may be in the form of, for example, a polyhydrate suchas a monohydrate or pentahydrate, or low hydrate such as a hemihydrate.

Examples of the forms of the hydrates of the compound of the presentinvention include a monohydrate, dihydrate, trihydrate and di- totri-hydrate. Further, examples of the forms of these hydrates include aclathrate hydrate. These hydrates can be obtained by precipitating thecompound represented by the general formula (I), N-oxide thereof,prodrug thereof or pharmaceutically acceptable salts thereof, or thecompound represented by the general formula (I-1), N-oxide thereof orpharmaceutically acceptable salt thereof from, for example, awater-containing organic solvent.

[Co-Crystal]

The compound represented by the general formula (I) or the like, N-oxidethereof, prodrug thereof, pharmaceutically acceptable salt thereof orsolvate thereof, and the compound represented by the general formula(I-1) or the like, N-oxide thereof, pharmaceutically acceptable saltthereof, or solvate thereof can be co-crystallized with an appropriateco-crystal forming agent. The co-crystal is preferably apharmaceutically acceptable one which can be co-crystallized with apharmaceutically acceptable co-crystal forming agent. A co-crystal isdefined as a crystal in which two or more different molecules are formedby intermolecular interactions different from ionic bonds. Further, theco-crystal may be a complex of a neutral molecule and a salt. Theco-crystal can be prepared by known methods, for example, by meltcrystallization, recrystallization front solvent or by physicallygrinding components together.

Examples of the appropriate co-crystal forming agents include thosedescribed in WO2006/007448, such as 4-aminobenzoic acid,4-aminopyridine, adenine, alanine, acetylsalicylic acid and the like.

[Radioisotopes]

The compound represented by the general formula (I) or the like, N-oxidethereof, prodrug thereof, pharmaceutically acceptable salt thereof orsolvate thereof and the compound represented by the general formula(I-1) or the like, N-oxide thereof, pharmaceutically acceptable saltthereof or solvate thereof may be labeled with an isotope or the like(e.g., ²H, ³H, ¹¹C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I,¹²⁵I, etc.). The examples include the compound in which all or part ofhydrogen atoms constituting one or more groups among R¹, R², R³, R⁴, R⁵,R⁶ and R⁷ in the general formula (I) or R¹, R^(2c), R³, R^(4a), R⁵,R^(6a) and R⁷ in the general formula (I-1) were replaced with heavywater atoms or tritium atoms, for example,4-(4-amino-2-fluoro-5-(methoxy-d₃)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amineand the like. In the present specification, “methyl-d₃” and “methoxy-d₃”represent a triduteriomethyl group and triduteriomethoxy group,respectively.

[Method for Producing Compounds of the Present Invention]

The compound of the present invention can be produced by appropriatelyimproving known methods, for example, the methods described inComprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc,1999), the methods below, the methods shown in Examples and the like andthen using them in combination.

Among the compounds represented by the general formula (I) or the like,the compound represented by the general formula (IV):

[wherein, all symbols have the same meanings as described above.] can beproduced by the method represented by the following Reaction Scheme 1.

[wherein, Pg represents a protecting group for an amino group (e.g.,tert-butoxycarbonyl group, benzyloxycarbonyl group, fluorenylcarbonylgroup, trityl group, o-nitrobenzenesulfenyl group or acetyl group), andR′ represents each independently a hydrogen atom, C1-5 alkyl group, C3-6cycloalkyl group, hydroxyl group or halogen atom, herein when R′represents a C1-5 alkyl group, two R's may form a dioxaborolane ringtogether with the adjacent oxygen atom and boron atom, and other symbolshave the same meanings as described above.)

Coupling Reaction 1 in Reaction Scheme 1 can be carried out by the knownSuzuki coupling reaction, for example, at 0 to 200° C., under thepresence or absence of 0.01 to 100 mol % of a palladium catalyst (e.g.,tetrakistriphenylphosphine palladium,bis(triphenylphosphine)palladium(II)dichloride,tris(dibenzylideneacetone)dipalladium, palladium acetate, palladiumacetylacetonate, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladiumdichloromethane complex orbis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium, etc.) and0.01 to 400 mol % of a phosphine ligand (e.g., triphenylphosphine,tri-tert-butylphosphine, tricyclohexylphosphine ordi(1-adamantyl)-n-butylphosphine or the like), in an organic solvent(e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol,ethanol, isopropyl alcohol, tetrahydrofuran, dimethyl formamide orN-methylpyrrolidone, etc.) alone or a mixed solvent with water, underthe presence or absence of 1 to 10 equivalents of a base (e.g.,potassium carbonate, sodium carbonate, cesium carbonate, sodiumhydroxide, potassium hydroxide, sodium phosphate, potassiumtriethylamine phosphate or N,N-diisopropylethylamine or the like), inthe presence of 1 to 10 equivalents of a boric acid reagent.

Further, Coupling Reaction 1 can also be carried out by a known couplingreaction using an organometallic reagent, for example, the Negishireaction using a zinc reagent instead of a boric acid reagent, the Stillreaction using a tin reagent instead of the boric acid reagent, theHiyama coupling using a silicon reagent instead of the boric acidreagent, and the Kumada reaction using a Grignard reagent instead of theboric acid reagent and a nickel catalyst instead of a palladium catalystare also performed.

Coupling Reaction 2 in Reaction Scheme 1 is also performed by the knownSuzuki coupling reaction, the Negishi reaction, the Still reaction, theHiyama coupling, the Kumada reaction, or the like.

The deprotection reaction in Reaction Scheme 1 can be carried out by aknown deprotection reaction under acidic conditions, for example, at 0to 100° C. in an organic solvent (e.g., dichloromethane, chloroform,dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran oranisole, etc.), in an organic acid (e.g., acetic acid, trifluoroaceticacid, methanesulfonic acid or p-tosylic acid, etc.) or inorganic acid(e.g., hydrochloric acid or sulfuric acid, etc.) or a mixture thereof(e.g., hydrogen bromide/acetic acid etc.), and in the presence orabsence of 2,2,2-trifluoroethanol.

The compound represented by the general formula (I-1) or the like inwhich none of R^(2d), R^(4a) and R^(6a) represents the preceding R^(FR)may be produced by the method represented by the preceding ReactionScheme 1.

Further, among the compounds represented by the general formula (I-1) orthe like, the compound represented by the general formula (V):

[wherein, R^(4b) represents —(CR^(Fb) ₂)_(q)OP(═O)(OR^(Fa)′)₂, R^(Fa)′represents each independently a hydrogen atom, C1-4 alkyl group, C3-6cycloalkyl group, —(CH₂)₂OH or —CH₂OCO₂CH(CH₃)₂ and other symbols havethe same meanings as described above.] is produced by subjecting thecompound represented by the general formula (IV) to the followingalkylation reaction, and if R^(Fa)′ is a protecting group, beingsubjected it to a deprotection reaction, if necessary.

[wherein, X¹ represents a halogen atom, and other symbols have the samemeanings as described above.]

Herein, the alkylation reaction is known, and for example, is carriedout by reacting X¹(CR^(Fb))_(q)OP(═O)(OR^(Fa)′)₂ with the compoundrepresented by the general formula (IV), in an organic solvent (e.g.,dichloromethane, chloroform, dioxane, ethyl acetate, methanol, ethanol,isopropyl alcohol, tetrahydrofuran, dimethylformamide,N-methylpyrrolidone and dimethyl sulfoxide, etc.), in the presence of aninorganic base (potassium carbonate, sodium carbonate, cesium carbonate,sodium hydroxide or potassium hydroxide, etc.) or organic base (e.g.,triethylamine, N,N-diisopropylamine, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide,tert-butylimino-tris(dimethylamino)phosphorane,tert-butylimino-tri(pyridino)phosphorane or1,4-diazabicyclo[2.2.2]octane, etc.). Further, in the case that R^(Fa)′is a protecting group, the deprotection reaction of R^(Fa)′ is alsoknown, and for example, it can be carried out by the known deprotectionreaction under acidic conditions or hydrogenation reaction in thepresence of palladium-carbon catalyst or the like. In addition, in thecase that R^(Fa)′ represents a protecting group, it corresponds to aprotective group for a hydroxyl group, of which examples include amethyl group, trityl group, methoxymethyl group, 1-ethoxyethyl group,methoxyethoxymethyl group, 2-tetrahydropyranyl group, trimethylsilylgroup, triethylsilyl group, tert-butyldimethylsilyl group,tert-butyldiphenylsilyl group, acetyl group, pivaloyl group, benzoylgroup, benzyl group, p-methoxybenzyl group, allyloxycarbonyl group or2,2,2-trichloroethoxycarbonyl group or the like. Further, thehydrogenation reaction in the presence of a palladium-carbon catalyst orthe like is carried out, for example, at room temperature to 120° C.,under a hydrogen gas atmosphere of 1 to 20 atm, in an organic solvent(e.g., methanol, ethanol, tetrahydrofuran, dioxane, ethyl acetate orisopropyl alcohol, etc.), in the presence of 0.01 to 100 mol % ofcatalyst (e.g., palladium-carbon, platinum-carbon, palladiumhydroxide-carbon or rhodium-carbon, etc.).

The compound represented by the general formula (IV-4) in ReactionScheme 1 can be produced by the method represented by the followingReaction Scheme 2.

The lithiation reaction in Reaction Scheme 2 can be carried out by aknown method, for example, by reacting a base (e.g., lithiumdiisopropylamide, n-butyllithium or tert-butyllithium, etc.) in anorganic solvent (e.g., tetrahydrofuran, diethylether, dioxane,dichloromethane, dichloroethane, n-hexane or toluene, or a mixed solventthereof, etc.), at −78° C. to room temperature, followed by addition ofcarbon dioxide (e.g., carbon dioxide gas or dry ice, etc.), and thenreacting it at −78° C. to room temperature.

The amidation reaction in Reaction Scheme 2 can be carried out by aknown method, for example, by reacting it to an acid halide agent (e.g.,oxalyl chloride or thionyl chloride, etc.) at −78° C. to refluxtemperature in an organic solvent (e.g., chloroform, dichloromethane,diethylether, tetrahydrofuran or dimethoxyethane, etc.) or undersolvent-free condition, and then reacting the obtained acid halide at−78° C. to reflux temperature, with addition of ammonia (e.g., ammoniagas, ammonia water or ammonia methanol solution, etc.), in the presenceor absence of a base (e.g., pyridine, triethylamine, dimethylaniline orN,N-dimethylaminopyridine, etc.).

The dehydration reaction in Reaction Scheme 2 can be carried out by aknown method, for example, by reacting it at −78° C. to the refluxtemperature, in the presence or absence of a solvent (e.g., chloroform,dichloromethane, diethylether, tetrahydrofuran or dimethoxyethane,etc.), in the presence or absence of a base (e.g., pyridine,triethylamine, dimethylaniline, N,N-dimethylaminopyridine orN,N-diisopropylethylamine, etc.), in the presence of a dehydrating agent(e.g., thionylchloride, trifluoroacetic anhydride, acetic anhydride,diphosphorus pentoxide or (methoxycarbonylsulfamoyl)triethylammoniumhydroxide inner salt, etc.).

The nucleophilic aromatic substitution reaction in Reaction Scheme 2 canbe carried out by a known method, for example, by reacting it at roomtemperature to 120° C., in an organic solvent (e.g., A,A-dimethylacetamide, N, A-dimethylformamide, tetrahydrofuran,acetonitrile, 2-propanol or dimethyl sulfoxide or a mixed solventthereof, etc.), in the presence of 1 to 10 equivalents of acetoxime anda base (e.g., re/V-butoxy potassium, ten-butoxy sodium, potassiumcarbonate, cesium carbonate, sodium hydrogen carbonate or tripotassiumphosphate, etc.).

The deprotection reaction in Reaction Scheme 2 can be carried out by aknown method, for example, a deprotection reaction under acidiccondition. For example, it can be carried out at 0 to 100° C., in anorganic solvent (e.g., dichloromethane, chloroform, dioxane,ethylacetate, methanol, isopropyl alcohol, tetrahydrofuran or anisole,etc.), in an organic acid (e.g., acetic acid, trifluoroacetic acid,methanesulfonic acid or p-tosylic acid, etc.) or an inorganic acid(e.g., hydrochloric acid or sulfuric acid, etc.) or a mixture thereof(e.g., hydrogen bromide/acetic acid etc.) in the presence or absence of2,2,2-trifluoroethanol.

The bromination reaction in Reaction Scheme 2 can be carried out by aknown method, for example, it can be carried out at −78° C. to 100° C.in an organic solvent (e.g., dichloromethane, chloroform,tetrahydrofuran, acetonitrile, dioxane, ethylacetate or acetic acid,etc.), in the presence or absence of 1 to 10 equivalents of abrominating agent (e.g., trimethylsilylbromide (TMSBr), bromine,hydrobromic acid or phosphorus tribromide, etc.) and 0.1 to 100 mol % ofcatalyst (e.g., copper (II) bromide or lithium bromide, etc.).

In the respective reactions in the present specification, the compoundsused as a starting material, compounds or reagents to be added, forexample, the compound represented by the general formula (IV-3) orgeneral formula (IV-5) and the compound used in the alkylation reactionor Reaction Scheme 2 are known or can be produced according to knownmethods or the methods described in Examples.

Among the compounds used in the present invention, the compounds havingoptical activity can be produced by using starting materials or reagentshaving optical activity, by optically resolving a racemic intermediateand then conducing to the compound to be used in the present invention,or by optically resolving a racemic compound. This method of opticalresolution is known, and for example, there is a method or the like toform a salt/complex with other optically active compounds and performrecrystallization, and then to isolate the desired compound or directlyseparate using a chiral column etc.

In the respective reactions in the present specification, the reactioninvolving heating can be performed using a water bath, oil bath, sandbath or microwave, as being apparent to those skilled in the art.

In the respective reactions in the present specification, a solid-phasesupported reagent supported on a high-molecular polymer (e.g.,polystyrene, polyacrylamide, polypropylene or polyethylene glycol, etc.)may be used as appropriate.

In the respective reactions in the present specification, the reactionproducts can be purified by conventional purification methods, forexample, methods such as distillation under normal pressure or reducedpressure, high performance liquid chromatography using silica gel ormagnesium silicate, thin layer chromatography, ion exchange resin,scavenger resin or column chromatography, washing, recrystallization andthe like. Purification may be carried out for respective reactions ormay be carried out after the completion of some reactions.

[Toxicity]

The compound of the present invention has sufficiently low toxicity andcan be safely used as a pharmaceutical.

[Application to Pharmaceuticals]

Since the compound of the present invention has agonistic activity toSTING, it can be prescribed as an effective agent for suppressing theprogression of, suppressing the recurrence of or treating cancer orinfectious disease.

In the present specification, examples of the term “treating cancer”include therapies (a) to decrease the proliferation of cancer cells, (b)to reduce symptoms caused by cancer, to improve the quality of life of apatient with cancer, (c) to reduce the dose of other alreadyadministered anti-cancer drugs or cancer therapeutic adjuvants and/or(d) to prolong the survival of a patient with cancer. And, the term“suppressing the progress of cancer” means to delay the progress ofcancer, to stabilize symptoms associated with cancer, and to reverse theprogress of symptoms. The term “suppressing the recurrence of cancer”means to prevent the recurrence of cancer in a patient of which cancerlesion had been completely or substantially eliminated or removed bycancer therapy or cancer resection surgery.

Further, in the present invention, the compound of the present inventioncan be prescribed to (a) a patient with cancer on which the therapeuticeffects of other anti-cancer drugs are insufficient or not sufficient,or patient with cancer worsened after treatment with other anti-cancerdrugs, (b) a patient with incurable or unresectable, metastatic,recurrent, refractory and/or distant metastatic cancer, (c) a patientwith cancer of which TPS or CPS is 50% or more, 25% or more, 10% ormore, 5% or more, or 1% or more, (d) a patient with MSI-H or dMMR cancer(e) a patient with BRAF V600E mutation-positive malignant melanoma ornon-small cell lung cancer, (f) a patient with EGFR genemutation-positive or ALK fusion gene-positive cancer, or (g) a patientwith TMB high frequency cancer.

Further, on the other hand, the compound of the present invention may berequired to be prescribed to (a) a patent with cancer which has not beentreated with any anti-cancer drugs, (b) a patient with cancer in whichTPS or CPS is less than 50%, less than 25%, less than 10%, less than 5%or less than 1%, (c) a patient with cancer without MSI-H and/or dMMR orwith MS1-L, (d) a patient with BRAF V600 wild type malignant melanoma ornon-small cell lung cancer, (e) a patient with EGFR genemutation-negative and/or ALK fusion gene-negative non-small cell lungcancer, or (g) a patient with TMB low frequency cancer.

Furthermore, it also can be prescribed as a postoperative adjuvanttherapy for preventively suppressing the recurrence or metastasis aftersurgical resection of cancer or as preoperative adjuvant therapyperformed before surgical resection.

Herein, examples of “other anti-cancer drugs” include the anti-cancerdrugs listed in the section [Combination and Combination preparation]below, that are, drugs exemplified, respectively, as alkylating agents,platinum preparations, antimetabolite antagonists (e.g., folatemetabolism, pyridine metabolism inhibitors and purine metabolisminhibitors), ribonucleotide reductase inhibitors, nucleotide analogs,topoisomerase inhibitors, microtubule polymerization inhibitors,microtubule depolymerization inhibitors, antitumor antibiotics, cytokinepreparations, anti-hormonal drugs, molecular targeting drugs, and cancerimmunotherapeutic drugs. Further, “the therapeutic effects of otheranti-cancer drugs am insufficient or not sufficient” means, for example,the case to be determined as stable (SD) or progression (PD) accordingto RECIST by even treatment with already-existing anti-cancer drugs.

Examples of cancers of which the progression and/or recurrence can besuppressed and/or which can be treated with the compound of the presentinvention include any solid cancers and blood cancers. Among solidcancers, examples of epithelial cell cancers include malignant melanoma(e.g., malignant melanoma in skin, oral mucosal epithelium, or orbit,etc.), non-small cell lung cancer (e.g., squamous non-small cell lungcancer and non-squamous non-small cell lung cancer), small cell lungcancer, head and neck cancer (e.g., oral cancer, nasopharyngeal cancer,oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivarygland cancer and tongue cancer), renal cell cancer (e.g., clear cellrenal cell cancer), breast cancer, ovarian cancer (e.g., serous ovariancancer and ovarian clear cell adenocarcinoma), nasopharyngeal cancer,uterine cancer (e.g., cervical cancer and endometrial cancer), analcancer (e.g., anal canal cancer), colorectal cancer (e.g., MSI-H and/ordMMR positive colorectal cancer), rectal cancer, colon cancer,hepatocellular carcinoma, esophageal cancer, gastric cancer,esophagogastric junction cancer, pancreatic cancer, urine urothelialcancer (e.g., bladder cancer, upper urinary tract cancer, ureteralcancer, renal pelvis cancer and urethral cancer), prostate cancer,fallopian tube cancer, primary peritoneal cancer, malignant pleuralmesothelioma, gallbladder cancer, bile duct cancer, biliary tractcancer, skin cancer (e.g., uveal melanoma and Merkel cell carcinoma),testicular cancer (germ cell tumor), vaginal cancer, vulvar cancer,penile cancer, small intestine cancer, endocrine system cancer, thyroidcancer, parathyroid cancer, adrenal carcinoma, spinal tumor,neuroblastoma, medulloblastoma, ocular retinoblastoma, neuroendocrinetumor, brain tumor (e.g., glioma (e.g., glioblastoma and gliosarcoma)and meningioma), squamous cell carcinoma and the like.

Among solid cancers, examples of sarcomas include bone/soft tissuesarcomas (e.g., Ewing sarcoma, pediatric rhabdomyosarcoma, endometrialleiomyosarcoma, chondrosarcoma, lung sarcoma, osteosarcoma andcongenital fibrosarcoma), Kaposi's sarcoma and the like.

Examples of blood cancers include multiple myeloma, malignant lymphoma(e.g., non-Hodgkin lymphoma (e.g., follicular lymphoma, precursor B-celllymphoblastic lymphoma, chronic B lymphocytic leukemia, nodal marginalzone B-cell lymphoma, diffuse large B-cell lymphoma, MALT lymphoma,splenic primary marginal zone B-cell lymphoma, hairy cell leukemia,primary mediastinal large B-cell lymphoma, Burkitt lymphoma, mantle celllymphoma, mycosis fungoides, Sezary syndrome, chronic or acutelymphocytic leukemia, precursor T cell lymphoblastic lymphoma, chronic Tlymphocytic leukemia, large granular T-cell leukemia, large granularNK-cell leukemia, peripheral T-cell lymphoma, extranodal NK/T-celllymphoma, adult T-cell leukemia, angiocentric lymphoma, intestinalT-cell lymphoma, Hodgkin-like/Hodgkin-related anaplastic large celllymphoma, B-cell lymphoblastic leukemia, T-cell lymphoblastic leukemiaand lymphoplasmacytoid lymphoma) and Hodgkin lymphoma (e.g., classicHodgkin lymphoma and nodular lymphoid predominant Hodgkin lymphoma)),leukemia (e.g., acute myelogenous leukemia and chronic myelogenousleukemia), central nervous system malignant lymphoma, myelodysplasticsyndromes, myeloproliferative syndromes and the like.

Further, examples of cancers of which the progression and/or recurrencecan be suppressed and/or which can be treated with the compound of thepresent invention include pediatric cancers and unknown primary cancers,as well.

Examples of infectious diseases of which the progression and/orrecurrence can be suppressed and/or which can be treated with thecompound of the present invention include symptoms caused by viralinfection, parasitic infection, bacterial infection or fungal infection.

Examples of viral infections include infectious diseases which arecaused by adenovirus, arenavirus, bunyavirus, calicivirus, coronavirus,filovirus, hepadnavirus, herpesvirus, orthomyxovirus, papovavirus,paramyxovirus, parvovirus, picomavirus, poxvirus, reovirus, retrovirus,rhabdovirus, togavirus, papillomavirus (e.g., human papillomavirus(HPV)), human immunodeficiency virus (HIV), poliovirus, hepatitis virus(e.g., hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis Cvirus (HCV), hepatitis D virus (HDV) and hepatitis E virus (HEV)),smallpox virus (e.g., variola major and variola minor), vaccinia virus,influenza virus, rhinovirus, dengue virus, equine encephalitis virus,rubella virus, yellow fever virus, Norwalk virus, human T-cell leukemiavirus (HTLV-I), hairy cell leukemia virus (HTLV-II), Californiaencephalitis virus, hanta virus (hemorrhagic fever), rabies virus, Ebolavirus, Marburg virus, measles virus, mumps virus, respiratory syncytialvirus (RSV), herpes simplex type 1 (oral herpes), herpes simplex type 2(genital herpes), herpes zoster (varicella-zoster virus),cytomegalovirus (CMV), Epstein-Barr virus (EBV), flavivirus,foot-and-mouth disease virus, Chikungunya virus, Lassa virus, arenavirusor oncovirus.

Examples of bacterial infection include infectious diseases caused byinfection with tubercle bacillus, anthrax, pathogenic bacterium, foodpoisoning bacterium, salmonella, staphylococcus, streptococcus, tetanusbacillus, mycobacteria, tetanus bacterium, plague bacterium, anthrax andantibiotic-resistant bacteria such as methicillin-resistantStaphylococcus aureus (MRSA), Clostridium difficile, or other infectiousbacterias.

Examples of fungal infection include infectious diseases caused byinfection with Aspergillus, Blastomyces dermatitisdis, Candida yeast(e.g., Candida albicans), Coccidioides, Cryptococcus neoformans,Cryptococcus gatti, dermatophyte, Fusarium, histoplasmosis capsulati,mucoromycotina, Pneumocystis jiroveci, Sprothrix schenckii, Exerohyrumor Cladosporium.

[Combination or Combination Preparation]

In order to (a) suppress the progression, and/or recurrence of and/orenhance the therapeutic effect on cancer or infectious disease, (b)decrease the dose of other combined drugs, and/or (c) reduce the sideeffects of other combined drugs, (d) enhance immunoenhancing effects ofother combined drugs, that is, as an adjuvant, the compound of thepresent invention or pharmaceutical composition containing the compoundof the present invention as an active ingredient (hereinafter,abbreviated as “the compound of the present invention or the like”) maybe used in combination with one or more kinds of other drugs. In thepresent invention, the formulation which is prescribed in combinationwith other drugs may be of a combination preparation which bothcomponents are mixed in one preparation or of separated preparations.The combination can compensate the effects in preventing, suppressingthe progression of, suppressing the recurrence of and/or treatingdisease with other drugs, and reduce the dose or frequency of itsadministration. In the case dial the compound of the present inventionor the like and other drugs are administered separately, both may beadministered simultaneously for a certain period, and then only thecompound of the present invention or the like or other drugs may beadministered alone. Further, the compound of the present invention orthe like may be administered initially, followed by administration withother drugs, or other drugs may be administered initially, followed byadministration with the compound of the present invention or the like.In the above administration, there may be a certain period in which bothdrugs are administered, simultaneously. Further, the administrationmethods of the respective drugs may be the same or different. Dependingon the nature of the drug, it can also be provided as a kit containingthe compound of the present invention and other drugs. Herein, the doseof other drugs can be appropriately selected based on a dose clinicallyused. Further, other drugs may be administered in combination of two ormore kinds of other drugs at an appropriate ratio. Furthermore, examplesof other drugs include those which would be found in the future, as wellas those which have been found to date.

In cancer treatment, examples of anti-cancer drugs which can be used incombination with the compound of the present invention or the likeinclude an alkylating agent (e.g., dacarbazine. Nimustine, Temozolomide,Fotemustine, bendamustine, Cyclophosphamide, Ifosfamide, Carmustine,Chlorambucil and Procarbazine, etc.), platinum preparation (e.g.,Cisplatin, Carboplatin, Nedaplatin and oxaliplatin, etc.),antimetabolite (e.g., folic acid antimetabolites (e.g., Pemetrexed,leucovorin and Methotrexate etc.), pyridine metabolism inhibitor (e.g.,TS-1) (Registered trademark), 5-fluorouracil, UFT, Carmofur,Doxifluridine, FdUrd, Cytarabine and Capecitabine, etc.), purinemetabolism inhibitor (e.g., Fludarabine, Cladribine and Nelarabine,etc.), ribonucleotide reductase inhibitor, nucleotide analogue (e.g.,Gemcitabine etc.)), topoisomerase inhibitor (e.g., Irinotecan, Nogitecanand Etoposide, etc.), microtubule polymerization inhibitor (e.g.,Vinblastine, Vincristine, Vindesine, Vinorelbine, Eribulin, etc.),microtubule depolymerization inhibitor (e.g., Docetaxel and Paclitaxel),antitumor antibiotic (e.g., Bleomycin, Mitomycin C, Doxorubicin,Daunorubicin, Idarubicin, Etoposide, Mitoxantrone, Vinblastine,Vincristine, Peplomycin, Amrubicin, Aclarubicin and Epirubicin, etc.),cytokine preparation (e.g., IFN-α2a, IFN-α2b, peg IFN-α2b, natural IFN-βand interleukin-2, etc.), anti-hormonal drug (e.g., Tamoxifen,Fulvestrant, Goserelin, Leuprorelin, Anastrozole, Letrozole andExemestane, etc.), molecularly targeted drug, cancer immunotherapeuticdrug and other antibody drugs, etc.

Herein, examples of the molecular targeting drug include an ALKinhibitor (e.g., Crizotinib, Ceritinib, Ensartinib, Alectinib andLorlatinib), BCR-ABL inhibitor (e.g., Imatinib and Dasatinib), EGFRinhibitor (e.g., Erlotinib, EGF816, Afatinib, Osimertinib mesylate,Gefitinib and Rociletinib), B-Raf inhibitor (e.g., Sorafenib,Vemurafenib, TAK-580, Dabrafenib, Encorafenib, LXH254, Emurafenib andBGB-3111), VEGFR inhibitor (e.g., Bevacizumab, Apatinib, Lenvatinib,Aflibercept and Axitinib), FGFR inhibitor (e.g., AZD4547, B-701, FGF401and INCB054828), c-Met inhibitor (e.g., Savolitinib, merestinib,Capmatinib, INC280 and Glesatinib), Ax1 inhibitor (e.g., ONO-7475 andBGB324), Mek inhibitor (e.g., Cobimetinib, Binimetinib, Selumetinib andTrametinib), CDK inhibitor (e.g., Dinaciclib, Abemaciclib, Palbocicliband trilaciclib), Btk inhibitor (e.g., ONO-4059, Ibrutinib andAcalabrutinib), PI3K-δ/γ inhibitor (e.g., TGR-1202, INCB050465 andIPI-549), JAK-1/2 inhibitor (e.g., Itacitinib and Ruxolitinib), ERKinhibitor (e.g., SCH 900353), TGFbR1 inhibitor (e.g., Galunisertib),Cancer cell sternness kinase inhibitor (e.g., Amcasertib), FAK inhibitor(e.g., Defactinib), Syk/FLT3 dual inhibitor (e.g., TAK-659), ATRinhibitor (e.g., AZD6738), Wee1 kinase inhibitor (e.g., AZD1775),Multi-tyrosine kinase inhibitor (e.g., Sunitinib, Pazopanib,Cabozantinib, Regorafenib, Nintedanib, Sitravatinib and Midostaurin),mTOR inhibitor (e.g., Temsirolimus, Everolimus, Vistuscrtib,Irinotecan), HDAC inhibitor (e.g., Vorinostat, Romideps). Entinostat,Chidamide, Mocetinostat, Citarinostat, Panobinostat, Valproate), PARPinhibitor (e.g., Niraparib, Olaparib, Veliparib, Rucaparib,Beigene-290), aromatase inhibitor (e.g., Exemestane, Letrozole), EZHazeinhibitor (e.g., tazemetostat), Galectin-3 inhibitor (e.g., GR-MD-02),STAT3 inhibitor (e.g., Napabucasin), DNMT inhibitor (e.g., Azacitidine),SMO inhibitor (e.g., Vismodegib), Hsp90 inhibitor (e.g., XL888),γ-tubulin specific inhibitor (e.g., Glaziovianin A, Plinabulin). HIF2ainhibitor (e.g., PT2385), glutaminase inhibitor (e.g., CB-839), E3ligase inhibitor (e.g., Avadomide), Nrf2 activator (e.g.,Omaveloxolone), arginase inhibitor (e.g., CB-1158), Cell cycle inhibitor(e.g., Trabectedin), Ephrin B4 inhibitor (e.g., sEphB4-HAS), IAPantagonist (e.g., Birinapant), anti-Her2 antibody (e.g., Trastuzumab,Trastuzumab emtansine, Pertuzumab and Margetuximab), anti-EGFR antibody(e.g., Cetuximab, Panitumumab, Necitumumab and Nimotuzumab). Anti-VEGFantibody (e.g., Bevacizumab), anti-VEGFR2 antibody (e.g., Ramucirumab),anti-CD20 antibody (e.g., Rituximab, Ofatumumab, IJblituximab andObinutuzumab), anti-CD30 antibody (e.g., Brentuximab Vedotin), anti-CD38antibody (e.g., Daratumumab), Anti-DR5 antibody (e.g., OS-8273a),anti-CA125 antibody (e.g., Oregovomab), anti-DLL4 antibody (e.g.,Demcizumab), anti-fucosyl GM1 antibody (e.g., BMS-986012), anti-gpNMBantibody (e.g., Glembatumumab vedotin), anti-Mesothelin antibody (e.g.,BMS-986148), anti-MMP9 antibody (e.g., Andecaliximab), anti-GD2 antibody(e.g., Dinutuximab-β), anti-c-Met antibody (e.g., ABT-399), anti-FOLR1antibody (e.g., Mirvetuximab soravtansine), anti-Ang2-VEGF bispecificantibody (e.g., Vanucizumab), Anti-CD30-CD16A bispecific antibody (e.g.,AFM13), anti-CD79b antibody (e.g., Polatuzumab Vedotin), anti-FAPantibody/IL-2 fusion protein (e.g., RO6874281), anti-CEA antibody/IL-2fusion protein (e.g., Cergutuzumab amunaleukin), anti-CEA-CD3 bispecificantibody (e.g., RO6958688), anti-DLL3 antibody (e.g., Rovalpituzumabtesirine), anti-CD3-CD19 bispecific antibody (e.g., Blinatumomab),anti-CD20-CD3 bispecific antibody (e.g., REGN1979) and the like.

Examples of cancer immunotherapeutic agents include an anti-PD-1antibody (e.g., Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab(MK-3475), Spartalizumab (PDR-001), Tislelizumab (BGB-A317), AMP-514(MED10680), Dostarlimab (ANB011/TSR-042), Tripalimab (JS001),Camrelizumab (SHR-1210), Genolitnzumab (CBT-501), Sintilimab (IBI308),STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003,HLX10, BAT-1306, AK105, AK103, B1 754091, LZM009, CMAB819, Sym021,GB226, SSI-361, JY034, HX008, ABBV181, BCD-100, PF-06801591, CX-188,JNJ-63723283 and AB122, etc.), anti-PD-L1 antibody (e.g., Atezolizumab(RG7446/MPDL3280A), Avelumab (PF-06834635/MSB0010718C), Durvalumab(MED14736), BMS-936559, STI-1014, KN035, LY3300054, HLX20, SHR-1316,CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001,FAZ053, CBT-502, JS003 and CX-072, etc.), PD-1 antagonist (e.g., eachcompound of AUNP-12 and BMS-M1 to BMS-M10 (see WO2014/151634,WO2016/039749, WO2016/057624, WO2016/077518, WO2016/100285,WO2016/100608, WO2016/126646, WO2016/149351, WO2017/151830 andWO2017/176608), BMS-1, BMS-2, BMS-3, BMS-8, BMS-37, BMS-200, BMS-202,BMS-230, BMS-242, BMS-1001 and BMS-1166 (sec WO2015/034820,WO2015/160641. WO2017/066227 and Oncotarget. 2017 Sep. 22; 8 (42):72167-72181.), Each compound of Incyte-1 to Incyte-6 (see WO2017/070089,WO2017/087777. WO2017/106634, WO2017/112730, WO2017/192961 andWO2017/205464), CAMC-1 to CAMC-4 (see WO2017/202273, WO2017/202274,WO2017/202275 and WO2017/202276), RG_1 (see WO2017/118762) and DPPA-1(see Angew. Chcm. Int. Ed. 2015, 54, 11760-11764), etc.), PD-L1/VISTAantagonist (e.g., CA-170 etc.), PD-L1/TIM3 antagonist (e.g., CA-327etc.), anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein(e.g., AMP-224 etc.), anti-CTLA-4 antibody (e.g., Ipilimumab (MDX-010),AGEN1884 and Tremelimumab, etc.), anti-LAG-3 antibody (e.g., Relatlimab(BMS-986016/ONO-4482), LAG525, REGN3767 and MK-4280, etc.), LAG-3 fusionprotein (e.g., IMP321 etc.), anti-Tim3 antibody (e.g., MBG453 andTSR-022, etc.), anti-KIR antibody (e.g., Lirilumab(BMS-986015/ONO-4483), IPH2101, LY3321367 and MK-4280, etc.), anti-BTLAantibody, anti-TIGIT antibody (e.g., Tiragolumab(MTIG-7192A/RG-6058/RO-7092284) and BMS-986207 (ONO-4686), etc.),anti-VISTA antibody (e.g., JNJ-61610588 etc.), anti-CD137 antibody(e.g., Urelumab (ONO-4481/BMS-663513) and Utomilumab (PF-05082566),etc.), anti-CSF-1R antibody/CSF-1R inhibitor (e.g., Cabiralizumab(FPA008/BMS-986227/ONO-4687), Emactuzumab (RG7155/RO5509554), LY3022855,MCS-110, JMC-CS4, AMG820, Pexidartinib, BLZ945 and ARRY-382, etc.),anti-OX40 antibody (e.g., MEDI6469, PF-04518600, MEDI0562, MEDI6383,Efizonerimod, GSK3174998, BMS-986178 and MOXR0916, etc.), anti-HVEMantibody, anti-CD27 antibody (e.g., Varlilumab (CDX-1127) etc.),anti-GITR antibody (e.g., MK-4166, INCAGN01876, GWN323 and TRX-518,etc.), anti-CD28 antibody, anti-CCR4 antibody (e.g., Mogamulizumabetc.), anti-B7-H3 antibody (e.g., Enoblituzumab etc.), anti-ICOS agonistantibody (e.g., JTX-2011 and GSK3359609, etc.), anti-CD4 antibody (e.g.,MTRX-1011A, TRX-1, Ibalizumab, huB-F5, Zanolimumab, 4162W94,Clenoliximab, Keliximab, AD-519, PRO-542, Cedelizumab, TNX-355,Dacetuzumab, Tregalizumab, Priliximab, MDX-CD4, CAMPATH-9 and IT1208,etc.), anti-DEC-205 antibody/NY-ESO-1 fusion protein (e.g., CDX-1401etc.), Anti-SLAMF7 antibody (e.g., Elotuzumab etc.), anti-CD73 antibody(e.g., Oleclumab and BMS-986179, etc.), anti-CD122 antibody (e.g.,NKTR-214 etc.), anti-CD40 agonist antibody (e.g., ABBV-428, APX005M andR07009789, etc.), IDO inhibitor (e.g., Epacadostat, Indoximod andBMS-986205, etc.), TLR agonist (e.g., Motolimod, CMP-001, G100,IMO-2125, SD-101 and MED19197, etc.), adenosine A2A receptor antagonist(e.g., Preladenant, AZD4635, PBF 509 and CPI-444, etc.), anti-NKG2Aantibody (e.g., Monalizumab etc.), anti-CSF-1 antibody (e.g., PD0360324etc.), immunopotentiator (e.g., PV-10 etc.), IL-15 super agonist (e.g.,ALT-803 etc.), soluble LAG3 (e.g., 1MP321 etc.), CD47 antagonist (e.g.,ALX148 etc.) and IL-12 antagonist (e.g., M9241 etc.) and the like.Incidentally, Nivolumab can be produced according to the methoddescribed in WO2006/121168, Pembrolizumab can be produced according tothe method described in WO2008/156712, BMS-936559 can be producedaccording to the method described in WO2007/005874, and Ipilimumab canbe produced according to the method described in WO2001/014424.

Further, examples of other antibody drugs include an anti-IL-1β antibody(e.g., Canakinumab etc.), anti-CCR2 antibody (e.g., Plozalizumab etc.)and the like.

[Prescription]

In order to use the compound of the present invention or the like, orthe combination of the compound of the present invention and other drugsfor the above purpose, it is usually administered systemically orlocally, orally or parenterally. The dose varies depending on age,weight, symptoms, therapeutic effects, administration methods, treatmenttime and the like, but usually, it is orally administered once per adultin the range of 1 ng to 2,000 mg once a day or several times a day, orit is parenterally administered once per adult in the range of 0.1 ng to200 mg once a day or several times a day, or intravenously administeredcontinuously in the range of 30 minutes to 24 hours per day. Of course,as described above, since the dose varies depending on variousconditions, a dose smaller than the above dose may be sufficient, or adose exceeding the range may be required.

[Formulation]

When a compound of the present invention or the like or a combination ofthe compound of the present invention and other drugs is administered, asolid preparation or liquid preparation for oral administration, asustained-release preparation or controlled-release preparation for oraladministration, or an injection, infusion, external preparation,inhalant, suppository or the like for parenteral administration is used.

Examples of the solid preparation for oral administration includetablets, pills, capsules, powders, granules and the like, and examplesof capsules include hard capsules, soft capsules and the like.

The solid preparation may be prepared, for example, by formulating thecompound of the present invention along with a pharmaceuticallyacceptable carrier. Herein, examples of the pharmaceutically acceptablecarrier used for formulating the solid preparations include an excipient(e.g., lactase, mannitol, glucose, microcrystalline cellulose andstarch), binder (e.g., hydroxylpropylcellulose, polyvinylpyrrolidone andmagnesium aluminometasilicate, etc.), disintegrant (e.g., calcium fibringlycolate etc.), lubricant (e.g., magnesium stearate etc.), stabilizer,solubilizer (e.g., glutamic acid and aspartic acid, etc.) and the like.If necessary, it may be coated with a coating agent (e.g., sucrose,gelatin, hydroxypropylcellulose or hydroxypropylmethylcellulosephthalate, etc.), or may be coated with two or more layers. Further, itmay be contained in a capsule containing gelatin.

The liquid preparation for oral administration may be in any form suchas aqueous solution, suspension, emulsion, syrup, elixir or the like.For example, the compound of the present invention may be dissolved,suspended or emulsified in a diluent (e.g., purified water, ethanol or amixed solution thereof or the like) to prepare a preparation. Further,the liquid preparation may contain a wetting agent, suspending agent,emulsifying agent, sweetening agent, flavoring agent, aromatic agent,preservative, buffering agent or the like.

The sustained-release preparation for oral administration may contain,for example, a gel-forming substance, and examples of the gel-formingsubstances include a gum arabic, agar, polyvinylpyrrolidone, sodiumalginate, propylene glycol alginate, carboxyvinyl polymer, carboxymethylcellulose, sodium carboxymethyl cellulose, guar gum, gelatin,hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylalcohol, methyl cellulose, hydroxyethyl methyl cellulose or the like.

The injection or infusion for parenteral administration may be in theform of aqueous solution, suspension or emulsion, and may be formulatedas a solid formulation with a pharmaceutically acceptable carrier sothat it can be dissolved, suspended or emulsified by adding a solvent(e.g., distilled water for injection, physiological saline, glucosesolution and isotonic solution (e.g., a solution of sodium chloride,potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax orpropylene glycol, etc.), etc.) when needed. Herein, examples of the“pharmaceutically acceptable carrier” include a stabilizer (e.g.,various amino acids, albumin, globulin, gelatin, mannitol, glucose,dextran, ethylene glycol, propylene glycol, polyethylene glycol,ascorbic acid, sodium hydrogen sulfite, sodium thiosulfate, sodiumedetate, sodium citrate and dibutylhydroxytoluene, etc.), solubilizer(e.g., alcohol (e.g., ethanol etc.)), polyalcohol (e.g., propyleneglycol, polyethylene glycol, etc.) and nonionic surfactant (e.g.,Polysorbate 20 (registered trademark), Polysorbate 80 (registeredtrademark) and HCO-50, etc.), etc.), suspending agent (e.g., glycerylmonostearate, aluminium monostearate, methyl cellulose, carboxymethylcellulose, hydroxymethyl cellulose and sodium lauryl sulfate, etc.),emulsifier (e.g., gum arabic, sodium alginate and tragacanth, etc.),soothing agent (e.g., benzyl alcohol, chlorobutanol and sorbitol, etc.),buffer (e.g., phosphate buffer, acetate buffer, borate buffer, carbonatebuffer, citrate buffer, Tris buffer, glutamate buffer and epsilonaminocaproate buffer, etc.), preservative (e.g., methyl paraoxybenzoate,ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate,chlorobutanol, benzyl alcohol, benzalkonium chloride, dehydro sodiumacetate, sodium edetate, boric acid and borax, etc.), antiseptic agent(e.g., benzalkonium chloride, paraoxybenzoic acid and chlorobutanol,etc.), pH adjuster (e.g., hydrochloric acid, sodium hydroxide,phosphoric acid and acetic acid, etc.), antioxidant and the like. As theantioxidant, for example, (1) a water-soluble antioxidant such asascorbic acid, cysteine hydrochloride, sodium bisulfate, sodiummetabisulfite, sodium sulfite or the like, (2) an oil-solubleantioxidant such as ascorbyl palmitate, butylated hydroxyanisole,butylated hydroxytoluene, lecithin, propyl gallate, α-tocopherol or thelike, and (3) a metal chelating agent such as citric acid,ethylenediaminetetraacetic acid, sorbitol, tartaric acid, phosphoricacid or the like, can be used.

The injection or infusion can be produced by sterilizing it in the finalstep or by an aseptic operation method, for example, filtering with afilter or the like, and then filling a sterile container. And, theinjection or infusion may be used by dissolving a sterile powderobtained by vacuum drying and freeze-drying (which may contain a powderof pharmaceutically acceptable carrier) in a suitable solvent beforeuse.

Examples of the forms of external preparation for parenteraladministration include a propellant, inhalant, spray, aerosol, ointment,gel, cream, poultice, patch, liniment, nasal drop, and the like.

Such a propellant, inhalant and spray may contain a stabilizer such assodium bisulfite other than commonly used diluents and buffers givingisotonicity, for example, an isotonic agent such as sodium chloride,sodium citrate or citric acid. The method for producing the sprays isdescribed in, for example, U.S. Pat. Nos. 2,868,691 and 3,095,355, indetail.

Examples of the inhalants include an inhalant liquid and inhalantpowder, and the liquid may be in a form of being dissolved or suspendedin water or other appropriate mediums before use. These inhalants can bemanufactured according to known methods, for example, in the case of theinhalant liquid, they can be prepared by appropriately mixing apreservative (e.g., benzalkonium chloride and paraben, etc.), coloringagent, buffer (e.g., sodium phosphate and sodium acetate, etc.),isotonicity agent (e.g., sodium chloride and concentrated glycerin,etc.), thickener (e.g., carboxyvinyl polymer etc.), absorption enhancerand the like, if necessary, and in the case of the inhalant powder, theycan be prepared by appropriately mixing a lubricant (e.g., stearic acidand salt thereof, etc.), binder (e.g., starch and dextrin, etc.),excipient (e.g., lactose and cellulose, etc.), coloring agent,preservative (e.g., benzalkonium chloride and paraben, etc.), absorptionenhancer and the like, if necessary. When administering the inhalantliquid, a nebulizer (e.g., atomizer and nebulizer, etc.) is usuallyused, while when administering the inhalant powder, an inhaler for apowdered medicine is usually used.

The ointment is prepared in a known or commonly used formulation, forexample, can be prepared by mixing or melting the compound of thepresent invention in an ointment base. Herein, the ointment base can beselected from known or commonly used ones, which is used by mixing with,for example, one or more kinds selected from a higher fatty acid orhigher fatty acid ester (e.g., adipic acid, myristic acid, palmiticacid, stearic acid, oleic acid, adipic acid ester, myristic acid ester,palmitic acid ester, stearic acid ester and oleic acid ester, etc.),waxes (e.g., beeswax, whale wax and ceresin, etc.), surfactant (e.g.,polyoxyethylene alkyl ether phosphate etc.), higher alcohol (e.g.,cetanol, stearyl alcohol and cetostearyl alcohol, etc.), silicone oil(e.g., dimethyl polysiloxane etc.), hydrocarbons (e.g., hydrophilicpetrolatum, white petrolatum, purified lanolin and liquid paraffin,etc.), glycols (e.g., ethylene glycol, diethylene glycol, propyleneglycol, polyethylene glycol and macrogol, etc.), vegetable oil (e.g.,castor oil, olive oil, sesame oil and turpentine oil, etc.), animal oil(e.g., mink oil, egg yolk oil, squalane and squalene, etc.), water,absorption promoter and anti-rash agent. Further, it may contain amoisturizing agent, preservative, stabilizer, antioxidant, flavoringagent or the like.

The gel is prepared in a known or commonly used formulation, forexample, can be prepared by melting the compound of the presentinvention in a gel base. Herein, the gel base is selected from known orcommonly used ones, which is used by mixing with, for example, one ormore kinds selected from a lower alcohol (e.g., ethanol and isopropylalcohol, etc.), gelling agent (e.g., carboxymethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose and ethyl cellulose,etc.), neutralizing agent (e.g., triethanolamine and diisopropanolamine,etc.), surfactant (e.g., polyethylene glycol monostearate etc.), gums,water, absorption promoter and anti-rash agent. Further, it may containa preservative, antioxidant, flavoring agent or the like.

The cream is prepared in a known or commonly used formulation, forexample, can be prepared by melting or emulsifying the compound of thepresent invention in a cream base. Herein, the cream base is selectedfrom known or commonly used ones, which is used by mixing with, forexample, one or more kinds selected from a higher fatty acid ester,lower alcohol, hydrocarbons, polyhydric alcohol (e.g., propylene glycoland 1,3-butylene glycol, etc.), higher alcohol (e.g., 2-hexyldecanol andcetanol, etc.), emulsifier (e.g., polyoxyethylene alkyl ethers and fattyacid esters, etc.), water, absorption promoter and anti-rash agent.Further, it may contain a preservative, antioxidant, flavoring agent orthe like.

The poultice is prepared in a known or commonly used formulation, forexample, can be prepared by melting the compound of the presentinvention in a poultice base and spreading and coating it on a supportas a kneaded product. Herein, the poultice base is selected from knownor commonly used ones, which is used by mixing with, for example, one ormore kinds selected from a thickener (e.g., polyacrylic acid,polyvinylpyrrolidone, arabic gum, starch, gelatin and methylcellulose,etc.), wetting agent (e.g., urea, glycerin and propylene glycol, etc.),filler (e.g., kaolin, zinc oxide, talc, calcium and magnesium, etc.),water, solubilizing agent, tackifier, and anti-rash agent. Further, itmay contain a preservative, antioxidant, flavoring agent or the like.

The patch is prepared in a known or commonly used formulation, forexample, can be prepared by melting the compound of the presentinvention in a patch base and spreading and coating it on a support.Herein, the patch base is selected from known or commonly used ones,which is used by mixing with, for example, one or more kinds selectedfrom a polymer base, fats and oils, higher fatty acid, tackifier andanti-rash agent. Further, it may contain a preservative, antioxidant,flavoring agent or the like.

The liniment is prepared in a known or commonly used formulation, forexample, can be prepared by dissolving, suspending or emulsifying thecompound of the present invention in one or more kinds selected fromwater, an alcohol (e.g., ethanol and polyethylene glycol, etc.), higherfatty acid, glycerin, soap, emulsifier, suspending agent and the like.Further, it may contain a preservative, antioxidant, flavoring agent orthe like.

The contents of all patent documents and non-patent documents orreferences explicitly cited in the present specification may beincorporated herein as part of the present specification.

The present invention will be described in more detail by the followingExamples, but the scope of the present invention is not limited thereto.Various changes or modifications can be made by those skilled in the artbased on the description of the present invention, and these changes ormodifications are also included in the present invention.

EXAMPLE

Hi-flash SI or Hi-flash NH in parentheses shown in the section of mediumpressure preparative liquid chromatography represents the type of columnused (Hi-flash SI: silica gel (manufactured by Yamazen Co., Ltd.),Hi-flash NH: aminopropyl group-supporting silica gel (manufactured byYamazen Co., Ltd.)).

LC-MS/ELSD was performed under the following conditions: [Column: YMCTriart C18 (particle size: 1.9×10⁻⁶ m; column length: 30×2.0 mm ID):flow rate: 1.0 mL/min; column temperature: 40° C.; mobile phase (A):0.1% trifluoroacetic acid solution; mobile phase (B): 0.1%trifluoroacetic acid-acetonitrile solution; gradient (show the ratio ofmobile phase (A):mobile phase (B)): [0 min] 95:5; [0.1 min] 95:5: [1.2min] 5:95; (1.4 min] 5:95; (1.41 min] 95:5; [1.5 min] 95:5; anddetector:UV(PDA), ELSD, MS]

Numerical values shown at NMR are the ¹H-NMR-measured values (chemicalshift values) when the measurement solvent described in the parenthesesis used.

The compound names used in the present specification are named by usingcomputer programs:ACD/Name (registered trademark) (version 6.00,manufactured by Advanced Chemistry Development Inc.), Chemdraw Ultra(version 12.0, manufactured by Cambridge Soft) or Lexichcm Toolkit(version 1.4.2, manufactured by OpenEye Scientific Software), whichgenerally names according to IUPAC rules, or named according to theIUPAC nomenclature.

Reference Example 1: Lithium 2-chloro-4-fluoro-5-iodonicotinate

2-chloro-4-fluoro-5-iodopyridine (CAS No. 1370534-60-3) (13.4 g) wasdissolved in tetrahydrofuran (hereinafter, abbreviated as THF) (50 mL)and cooled to −78° C. Then, lithium diisopropylamide (1 mol/L THFsolution, 50 mL) was added dropwise thereto over 30 minutes. Afterstirring at −78° C. for 1.5 hours, finely crushed dry ice (11.4 g) wasadded thereto, which was stirred at −78° C. for 30 minutes. The reactionsolution was warmed to room temperature and the resulting precipitatewas collected by filtration to give the title compound (16.5 g) havingthe following physical property value.

LCMS retention time (min): 0.63;

MS (ESI, Pos.): 302 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.44 (d, J=9.0 Hz, 1H).

Reference Example 2:2-chloro-4-fluoro-3-iodonicotinonitrile

A mixture of the compound (16.0 g) prepared in Reference Example 1, N,N-dimethylformamide (hereinafter, abbreviated as DMF) (0.20 mL) andthionyl chloride (38.0 mL) was stirred at 80° C. for 3.5 hours. Thereaction solution was concentrated, and the THF solution dissolving theresidue obtained therefrom (100 mL) was cooled to 0° C., to whichsaturated aqueous ammonia (28%, 10.8 mL) was added dropwise withstirring. After stirring for 30 minutes, tap water was added to thereaction mixture, which was extracted with ethyl acetate. The organiclayer was washed with saturated saline, dried over sodium sulfate, andconcentrated. The residue obtained therefrom was used in the next stepwithout purification.

The crude product obtained by the above operation was dissolved in THF(174 mL), to which pyridine (21.1 mL) and trifluoroacetic anhydride(10.9 mL) were added under ice cooling, of which the mixture was stirredat 0° C. for 1 hour. A saturated aqueous sodium hydrogen carbonatesolution was added to the reaction solution, of which the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline, dried over sodium sulfate, and concentrated. Theresidue obtained therefrom was purified by silica gel chromatography(Hi-flash SI) (hexane:ethyl acetate=0:100 to 70:30) to give the titlecompound (5.82 g) having the following physical property value.

LCMS retention time (min): 0.92;

MS (ESI, Pos.): 283 (M+H)⁺;

¹H-NMR (CDCl₃): δ 8.83 (d, J=7.7 Hz, 1H).

Reference Example 3:2-chloro-S-iodo-4-((propan-2-ylideneamino)oxy)nicotinonitrile

Sodium tert-butoxide (9.02 g) was added to the THF solution (100 mL)dissolving propan-2-one oxime (6.86 g) at room temperature, of which themixture was stirred for 1 hour (hereinafter, this solution is referredto as an oxime solution). The oxime solution was added dropwise to THFsolution (90 mL) dissolving the compound (26.5 g) produced in ReferenceExample 2 over 15 minutes under ice cooling. After the temperature ofthe reaction solution was raised to room temperature, it was furtherstirred for 30 minutes. A saturated ammonium chloride aqueous solutionwas added thereto, of which the mixture was extracted with ethylacetate. The organic layer was washed with saturated saline, dried oversodium sulfate, and concentrated. The residue obtained therefrom waspurified by silica gel column chromatography (Hi-flash SI) (hexane:ethylacetate=70:30) to give the title compound (31.1 g) having the followingphysical property value.

LCMS retention time (min): 1.02;

¹H-NMR (CDCl₃): δ 8.67 (s, 1H), 2.21 (s, 3H), 2.13 (s, 3H).

Reference Example 4: 4-chloro-7-iodoisoxazolo[4,5-c]pyridin-3-amine

5 mol/L hydrochloric acid (70 mL) was added to ethanol solution (70 mL)dissolving the compound (4.66 g) produced in Reference Example 3, ofwhich the mixture was stirred at 70° C. for 1 hour. The solid formed inthe reaction solution was collected by filtration to give the titlecompound (2.93 g) having the following physical property value.

LCMS retention time (min): 0.76;

MS (ESI, Pos.): 296 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.65 is, 1H), 6.59 (s, 2H).

Bromotrimethylsilane (14.9 mL) was added to propionitrile solution (55.5mL) dissolving the compound (5.55 g) produced in Reference Example 4 atroom temperature, which was stirred at 105° C. for 3 hours. The reactionsolution was cooled to room temperature, to which saturated aqueoussodium hydrogen carbonate solution was added, of which the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline, dried over sodium sulfate, and concentrated. To theresidue obtained therefrom, hexane-ethyl acetate mixed solvent (4:1, 50mL) was added, of which the mixture was stirred for 30 minutes. Theprecipitate therein was collected by filtration to give the titlecompound (4.78 g) having the following physical property value.

LCMS retention time (min): 0.81;

MS (ESI, Pos.): 340 (M+H)⁺;

¹H-NMR (CDCl₃): δ 8.64 (s, 1H), 6.48 (s, 2H).

Reference Example 6:4-bromo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine

Under nitrogen atmosphere,1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.73 g)(CAS No. 1003846-21-6),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (484 mg)and 2 mol/L tripotassium phosphate aqueous solution (5.9 mL) was addedto 1,4-dioxane solution (25 mL) dissolving the compound (2.01 g)prepared in Reference Example 5 (2.01 g), of which the mixture wasstirred at 90° C. for 4 hours. The reaction solution was cooled to roomtemperature, diluted with ethyl acetate, and the insoluble materialtherein was filtered through a short silica gel pad. Water was added tothe obtained filtrate, of which the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried oversodium sulfate, and concentrated. To the residue obtained therefrom,methanol (10 mL) was added, of which the mixture was stirred for 30minutes. The precipitate therein was collected by filtration to give thetitle compound (1.50 g) having the following physical property value.

LCMS retention time (min): 0.80;

MS (ESI, Pos.): 364 (M+H)⁺.

Reference Example 7: (5-bromo-4-fluoro-2-nitrophenyl)(methyl)sulfane

(1-bromo-2,5-fluoro-2-nitrophenyl)(methyl)sulfane (CAS No. 167415-27-2)(2.00 g) was dissolved in DMF solution (20 mL) and cooled to 0° C. Anaqueous solution (4.2 mL) dissolving sodium thiomethoxide (707 mg) wasadded dropwise thereto, of which the mixture was stirred under icecooling for 1.5 hours. The resulting precipitate therein was collectedby filtration and dried to give the title compound (1.17 g) having thefollowing physical property value.

LCMS retention time (min): 1.05;

¹H-NMR (CDCl₃): δ 8.06 (d, J=8.0 Hz, 1H), 7.52 (d, J=6.0 Hz, 1H), 2.52(s, 3H).

Reference Example 8: 4-bromo-5-fluoro-2-(methylthio)aniline

Iron powder (1.23 g) was added to acetic acid solution (12 mL)dissolving the compound (1.17 g) produced in Reference Example 7, ofwhich the mixture was stirred at 90° C. for 1 hour. The reactionsolution was cooled to room temperature, filtered through Celite(Registered trademark), and the obtained filtrate was concentrated. Theresidue obtained therefrom was purified by silica gel columnchromatography (Hi-flash NH) (hexane:ethyl acetate=90:10 to 70:30) togive the title compound (1.06 g) having the following physical propertyvalue.

LCMS retention time (min): 1.01;

MS (ESI, Pos.): 236 (M+H);

¹H-NMR (CDCl₃): δ 7.52 (d, J=7.5 Hz, 1H), 6.50 (d, J=10.5 Hz, 1H), 4.45(brs, 2H), 2.31 (s, 3H).

Reference Example 9: 4-bromo-5-fluoro-2-(methylsulfonyl)aniline

Under ice cooling, metachloroperbenzoic acid (containing about 30%water) (1.41 g) was added to dichloromethane solution (8.0 mL)dissolving the compound (500 mg) produced in Reference Example 8. Afterstirring it under ice-cooling for 1 hour, 10% sodium thiosulfate aqueoussolution and saturated sodium hydrogencarbonate aqueous solution wereadded thereto to stop its reaction, of which the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over sodium sulfate, and concentrated. The residue obtainedtherefrom was purified by silica gel column chromatography (Hi-flash SI)(hexane:ethyl acetate=90:10 to 50:50) to give the title compound (487mg) having the following physical property value.

LCMS retention time (min): 0.82;

MS (ESI, Pos.): 268 (M+H)⁺.

Under nitrogen atmosphere, 4-bromo-5-fluoro-2-iodoaniline (CAS No.1219741-79-3) (810 mg), copper (I) iodide (48.8 mg),tributyl(1-ethoxyvinyl)tin (1.04 mL) and acetonitrile (10 mL) weremixed, of which the mixture solution was deaerated.Bis(triphenylphosphine)palladium (II) dichloride (180 mg) was addedthereto, of which the mixture was stirred at 80° C. for 5 hours. Thereaction solution was directly purified by silica gel columnchromatography (Hi-flash SI) (hexane:ethyl acetate=100:0 to 70:30) togive the title compound (547 mg) having the following physical propertyvalue.

LCMS retention time (min): 0.91;

MS (ESI, Pos.): 232 (M+Hf

Reference Example 11: 2-amino-5-bromo-N-ethyl-4-fluorobenzamide

A mixture of 2-amino-5-bromo-4-fluorobenzoic acid (CAS No. 143945-65-7)(2.20 g),1-(bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidehexafluorophosphate (HATU: CAS No. 148893-10-1) (4.60 g), N,N-diisopropylethylamine (2.4 mL) and DMF (47 mL) was stirred at roomtemperature for 2 hours. To the reaction solution, saturated aqueoussodium hydrogen carbonate solution was added, of which the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline, dried over sodium sulfate, and concentrated. Theresidue obtained therefrom was purified by silica gel columnchromatography (Hi-flash SI) (hexane:ethyl acetate=90:10 to 60:40) togive the title compound (2.08 g) having the following physical propertyvalue.

LCMS retention time (min): 0.84;

MS (ESI, Pos.): 261 (M+H)⁺.

Reference Example 12:5-fluoro-2-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Under nitrogen atmosphere, 1,4-dioxane (8.0 mL) was added to a mixtureof the compound (487 mg) produced in Reference Example 9,bis(pinacolato)diboron (922 mg) and potassium acetate (713 mg), of whichthe mixture was degassed.[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethanecomplex (148 mg) was added thereto, of which the mixture was stirred at90° C. overnight. The reaction mixture was filtered through Celite(registered trademark), and the obtained filtrate was concentrated. Theresidue obtained therefrom was purified by silica gel columnchromatography (Hi-flash SI) (hexane:ethyl acetate=100:0 to 80:20) togive the title compound (342 mg) having the following physical propertyvalue.

LCMS retention time (min): 0.91;

MS (ESI, Pos.): 316 (M+H)⁺.

Reference Examples 12(1) to 12(5)

In place of 4-bromo-5-fluoro-2-(methylsulfonyl)aniline of ReferenceExample 9, the bromoaryl compound corresponding to it was used, and bysubjecting it to the same operation as in Reference Example 12, thetitle compound having the following physical property value wasobtained.

Reference Example 12(1): methyl2-amino-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

LCMS retention time (minutes): 1.04;

MS (ESI, Pos.): 296 (M+H)⁺.

Reference Example 12(2):5-fluoro-2-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

LCMS holding time (min): 1.06;

MS (ESI, Pos.): 284 (M+H)⁺.

Reference Example 12(3):1-(2-amino-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one

LCMS retention lime (min): 0.99;

MS (ESI, Pos.): 280 (M+H)⁺.

Reference Example 12(4):2-amino-N-ethyl-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

LCMS retention time (minutes): 0.91;

MS (ESI, Pos.): 309 (M+H)⁺.

Reference Example 12(5):2-amino-4-chloro-N-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

LCMS holding time (minutes): 1.14;

MS (ESI, Pos.): 325 (M+H)⁺.

Reference Example 13: methyl2-amino-5-(3-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate

Under nitrogen atmosphere, the boronic acid ester (89.1 mg) produced inReference Example 12(1) andbis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium (19.4 mg)and 2 mol/L sodium carbonate aqueous solution (0.27 mL) were added toDMF solution (l 0.37 mL) dissolving the compound (100 mg) produced inReference Example 6, of which the mixture was stirred at 110° C. for 2hours. After cooling it to room temperature, tap water was addedthereto, of which the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated saline, dried over sodiumsulfate, and concentrated. The residue obtained therefrom was purifiedby silica gel column chromatography (Hi-flash SI) (hexane:ethylacetate=95:5 to 20:80) to give the title compound (110 mg) having thefollowing physical property value.

LCMS retention time (min): 0.75;

MS (ESI, Pos.): 453 (M+H)⁺.

Example 1: methyl2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate

Trifluoroacetic acid (4.0 mL) was added to dichloromethane solution (4.0mL) dissolving the compound (388 mg) produced in Reference Example 13,of which the mixture was stirred at 40° C. for 5 hours. To the reactionsolution, saturated sodium hydrogen carbonate was added, of which themixture was extracted with ethyl acetate. The organic layer was washedwith saturated saline, dried over sodium sulfate, and concentrated. Theresidue obtained therefrom was purified by silica gel columnchromatography (Hi-flash SI) (hexane:ethyl acetate=90:10 to 0:100) togive the compound of the present invention (19.6 mg) having thefollowing physical property value.

LCMS retention time (min): 0.59;

MS (ESI, Pos.): 369 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.86 (s, 1H), 8.34 (s, 2H), 8.05 (d, J=8.5 Hz, 1H),6.66 (d, J=12.5 Hz. 1H). 3.85 (s, 3H).

Example 2:4-(4-amino-2-fluoro-5-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-aminehydrochloride

Under nitrogen atmosphere,5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(CAS No. 1326283-60-6) (224 mg), bis[tri-tert-butylphosphine]palladium(65.9 mg), and 2 mol/L tripotassium phosphate aqueous solution (1.1 mL)were added to 1,4-dioxane solution (7.1 mL) dissolving the compound (235mg) produced in Reference Example 6, of which the mixture was stirred at110° C. for 3 hours. The reaction solution was directly purified bysilica gel column chromatography (Hi-flash SI) (hexane:ethyl acetate100:0 to 0:100) to give4-(4-amino-2-fluoro-5-methoxyphenyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine(108 mg) was obtained.

Hydrochloric acid (10% methanol solution, 2.0 mL) was added to THFsolution (2.2 mL) dissolving this compound (108 mg), of which tiremixture was stirred at room temperature for 2 hours. To the reactionsolution, saturated sodium hydrogen carbonate was added, of which themixture was extracted with ethyl acetate-methanol (9:1). The organiclayer was washed with saturated saline, dried over sodium sulfate andconcentrated. Tire residue obtained therefrom was purified by silica gelcolumn chromatography (Hi-flash SI) (ethyl acetate:methanol=100:0 to90:10). After concentration, the obtained residue was dissolved inmethanol (5.0 mL), to which hydrochloric acid (10% methanol solution,0.8 mL) was added, of which the mixture was concentrated. To theobtained residue, ethyl acetate (50 mL) was added, of which the mixturewas stirred under heating reflux for 1 hour and then concentrated togive the compound of the present invention ($7 mg) having the followingphysical property value.

LCMS retention time (min): 0.54;

MS (ESI, Pos.): 341 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.96 (s, 1H), 8.44 (s, 2H), 7.11 (d, J=6.5 Hz, 1H),6.70 (d, J=12.0 Hz, 1H), 3.93 (s, 3H).

Example 3:1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)ethan-1-one

Under nitrogen atmosphere, the boronate ester (10.7 g) prepared inReference Example 12 (3), butyl di-1-adamantylphosphine (984 mg),palladium acetate (308 mg), potassium iodide (456 mg) and 2 mol/Ltripotassium phosphate aqueous solution (28 mL) were added to1-methyl-2-pyrrolidone solution (hereinafter, abbreviated as NMP) (100mL) dissolving the compound (10.0 g) produced in Reference Example 6, ofwhich the mixture was stirred at 50 to 60° C. for 45 hours. Afterallowing the reaction solution to cool, insoluble matters therein wereremoved by filtration while washing with NMP. To the obtained filtrate,tap water (240 mL) was added little by little, of which the mixture wasstirred for 40 minutes, and the precipitated solid therein was collectedby filtration. The obtained solid was sequentially washed withacetonitrile (80 mL, twice) and methyl tert-butyl ether (80 mL, twice)by slurry washing, and then filtered and dried to give1-(2-amino-5-(3-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)ethan-1-one(8.52 g).

To this compound (6.00 g), methanol (24 mL) and methanesulfonic acid(3.96 g) were added, of which the mixture was stirred at 55 for 3 hours.The reaction mixture was allowed to cool to room temperature, andtriethylamine (18 mL) was added thereto, of which the mixture wasstirred at 55° C. for 2.5 hours. After allowing it to cool, theresulting precipitate was filtered to obtain a beige powder. To thepowder, methanol (40 mL) was added, of which the mixture was washed byslurry washing at room temperature, filtered, and dried to obtain thecompound of the present invention (4.50 g) having the following physicalproperty value.

LCMS retention time (min): 0.56;

MS (ESI, Pos.): 353 (M+H)⁺;

¹H-NMR (DMSO-ds): δ 13.3 (s, 1H), 8.97 (s, 1H), 8.47 (s, 1H), 8.23 (s,1H), 7.98 (d, J=8.5 Hz, 1H), 7.71 (brs, 2H), 6.67 (d, J=13.0 Hz, 1H),5.73 (s, 2H), 2.52 (s, 3H).

Example 4;4-(4-amino-2-fluoro-5-(methylthio)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-aminehydrochloride

To THF solution (1.5 mL) dissolving4-(4-amino-2-fluoro-5-(methylthio)phenyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine(76.6 mg) obtained by using the boronate ester produced in ReferenceExample 12(2) in place of methyl2-amino-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoateprepared in Reference Example 12(1) and subjecting it to the sameoperation as that in Reference Example 13, hydrochloric acid (10%methanol solution, 1.1 mL) was added at room temperature, of which themixture was stirred for 1 hour. After the reaction, the resultingprecipitate was collected by nitration to obtain the compound of thepresent invention (76.1 mg) having the following physical propertyvalue.

LCMS retention lime (min): 0.60;

MS (ESI, Pos.): 357 (M+H)⁺;

¹H-NMR (CD₃OD): δ 9.05 (s, 1H), 8.53 (s, 2H), 7.76 (d, J=8.0 Hz, 1H),6.78 (d, J=13.0 Hz, 1H), 2.41 (s, 3H).

Examples 4(1) to 4(16)

In place of4-(4-amino-2-fluoro-5-(methylthio)phenyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,the compound corresponding to it was prepared by a procedure similar tothat described in Example 4, and then subjected to a procedure similarto that described in Example 4, following that, to give the compound ofthe present invention having the following physical property value.

Example 4(1):4-(4-amino-3-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-aminehydrochloride

LCMS retention time (Min): 0.51;

MS (ESI, Pos.): 323 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.99 (s, 1H), 8.49 (s, 2H), 7.52 (s, 1H), 7.42 (d,J=7.0 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 4.05 (s, 3H).

Example 4(2):4-(4-amino-2-fluoro-5-(methoxy-d₃)phenyl-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridine-3-aminehydrochloride

LCMS retention time (min): 0.55;

MS (ESI, Pos.): 344 (M+H)⁺;

¹H-NMR (CD₃OD): δ 9.09 (s, 1H), 8.56 (s, 2H), 7.29 (d, J=5.5, 1H), 6.95(d, J=9.0 Hz, 1H).

Example 4(3):4-(4-amino-2-fluoro-5-(methylsulfonyl)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-aminehydrochloride

LCMS retention time (min): 0.55;

MS (ESI, Pos.): 389 (M+H)⁺;

¹H-NMR (CD₃OD): δ 9.10 (s, 1H), 8.50 (s, 2H), 8.12 (d, J=8.0, 1H), 6.90(d, J=12.5 Hz, 1H). 3.17 (s, 3H).

Example 4(4):4-(4-amino-2-fluoro-3-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-aminehydrochloride

HPLC retention time (min): 0.55;

MS (ESI, Pos.): 341 (M+H)⁺;

¹H-NMR (CD₃OD): δ 9.04 (s, 1H), 8.49 (s, 2H), 7.24 (dd, J=8.5, 7.5, 1H),6.84 (d, J=8.5 Hz, 1H), 3.99 (s, 3H).

Example 4(5):2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzamidehydrochloride

LCMS retention time (min): 0.50;

MS (ESI, Pos.): 354 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 9.03 (s, 1H), 8.40 (s, 2H), 7.92 (d, J=9.0, 1H),7.79 (br s, 1H), 7.23 (br s, 1H), 6.64 (d, J=12.0 Hz, 1H), 5.98 (br s,2H).

Example 4(6): ethyl2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoatehydrochloride

LCMS retention time (min): 0.69;

MS (ESI, Pos.): 383 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ9.01 (s, 1H), 8.38 ($, 2H), 7.99 (d, J=8.5, 1H), 7.30(br s, 1H), 6.72 (d, J=13.0 Hz, 1H), 5.83 (br s, 2H), 4.28 (q, J=7.0 Hz,2H), 1.29 (t, J=7.0 Hz, 3H).

Example 4(7):1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)propan-1-onehydrochloride

LCMS retention time (min): 0.77;

MS (ESI, Pos.): 367 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.94 (s, 1H), 8.38 (s, 2H), 8.20 (d, J=8.5 Hz, 1H),6.66 (d, J=13.0 Hz, 1H), 2.94 (q, J=7.0 Hz, 2H), 1.09 (t, J=7.0 Hz, 3H).

Example 4(8):2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-ethyl-4-fluorobenzamidehydrochloride

LCMS retention time (min): 0.70;

MS (ESI, Pas.): 382 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.98 (s, 1H), 8.41 (s, 2H), 7.85 (d, J=8.0 Hz, 1H),6.65 (d, J=13.0 Hz, 1H), 3.29 (q, J=7.0 Hz, 2H), 1.11 (t, J=7.0 Hz, 3H).

Example 4(9):1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)phenyl)ethan-1-onehydrochloride

LCMS retention time (min): 0.67;

MS (ESI, Pos.): 335 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.86 (s, 1H), 8.37 (s, 2H), 8.29 (d, J=2.0 Hz, 1H),7.64 (dd, J=9.0, 2.0 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 2.56 (s, 3H).

Example 4(10): methyl2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)benzoatehydrochloride

LCMS retention time (Min): 0.71;

MS (ESI, Pos.): 351 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 9.00 (s, 1H), 8.45 (s, 2H), 8.21 (s, 1H), 7.71 (d,J=9.0 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.02 (br s, 2H), 3.84 (s, 3H).

Example 4(11):2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-propylbenzamidehydrochloride

LCMS retention time (min): 0.70;

MS (ESI, Pos.): 378 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.86 (s, 1H), 8.38 (s, 2H), 7.95 (d, J=2.0 Hz, 1H),7.60 (dd, J=8.5, 2.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 3.26-3.13 (m, 2H),1.54 (q, J=7.0 Hz, 2H), 0.90 (t, J=7.0 Hz, 3H).

Example 4(12):1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)butan-1-onehydrochloride

LCMS retention time (min): 0.90;

MS (ESI, Pos.): 381 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.94 (s, 1H), 8.37 (s, 2H), 8.20 (d, J=8.0 Hz, 1H),6.65 (d, J=13.0 Hz, 1H), 2.88 (t, J=7.0 Hz, 2H), 1.65 (q, J=7.5 Hz, 2H),0.90 (t. J=7.5 Hz, 3H).

Example 4(13):1-(2-amino-S-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)phenyl)butan-1-onehydrochloride

LCMS retention time (min): 0.87;

MS (ESI, Pos.): 363 (M+H)⁺;

¹H NMR (CD₃OD): δ 8.86 (s, 1H), 8.38 (s, 2H), 8.33 (d, J=2.0 Hz, 1H),7.63 (dd, J=9.0, 2.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 2.96 (t, J=7.5 Hz,2H), 1.70-1.64 (m, 2H), 0.92 (t, J=7.0 Hz, 3H).

Example 4(14): 2-hydroxyethyl2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoatehydrochloride

LCMS retention time (min): 0.76;

MS (ESI, Pos.): 399 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.97 (s, 1H), 8.39 (s, 2H), 8.30 (d, J=8.5 Hz, 1H),6.69 (d, J=3.0 Hz, 1H), 4.26 (t, J=5.0 Hz, 2H), 3.74 (t, J=5.0 Hz, 2H).

Example 4(15):2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-methylbenzamidehydrochloride

LCMS mention time (min): 0.69;

MS (ESI, Pos.): 350 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 9.04 (s, 1H), 8.56 (d, J=4.5 Hz, 1H), 8.52 (s, 2H),8.18 (d, J=2.0 Hz, 1H), 7.64 (dd, J=8.5, 2.0 Hz, 1H), 6.94 (d, J=8.5 Hz,1H), 6.22 (s, 2H), 2.78 (d, J=4.5 Hz, 3H).

Example 4(16);4-(4-amino-2-chloro-5-(methylthio)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-aminehydrochloride

LCMS retention time (min): 0.63;

MS (ESI, Pos.): 373 (M+H)>;

¹H-NMR (DMSO-d₆): δ 9.08 (s, 1H), 8.43 (s, 2H), 7.40 (s, 1H), 6.93 (s,1H), 2.37 (s, 3H).

Examples 4(17) to 4(24)

In place of4-(4-amino-2-fluoro-5-(methylthio)phenyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,the compound corresponding to it was prepared by a procedure similar tothat described in Example 4, and purified by reverse phase HPLC (usedcolumn: YMC Triart C18 (30 mm×75 mm); mobile phase: 0.1%TFA/water/acetonitrile=95:5 to 60:40) to obtain the compound of thepresent invention having the following physical property value.

Example 4(17):2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluoro-N-methylbenzamidetrifluoroacetate

LCMS retention lime (min): 0.66;

MS (ESI, Pos.): 368 (M+H)⁺;

¹H-NMR (DMSO-ds): δ (rotamer mixture) 8.98 (s, 1H), 8.35 (s, 2H),8.27-8.21 (m, 1H), 7.76 (d, J=8.5 Hz, 1H), 6.61 (d, J=12.5 Hz, 1H), 5.69(br s, 2H), 2.71 (s, 1.5H), 2.69 (s, 1.5H).

Example 4(18):4-(4-amino-5-(ethylthio)-2-fluorophenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-aminetrifluoroacetate

LCMS retention time (min): 0.64;

MS (ESI, Pos.): 371 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.97 (s, 1H), 8.43 (s, 2H), 7.69 (d, J=8.0 Hz, 1H),6.73 (d, J=12.5 Hz, 1H), 2.81 (q, J=7.0 Hz, 2H), 1.25 (t, J=7.0 Hz, 3H).

Example 4(19):2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluoro-N-propylbenzamidetrifluoroacetate

LCMS retention time (min): 0.84;

MS (ESI, Pos.): 396 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.82 (s, 1H), 8.31 (s, 2H), 7.67 (d, J=8.0 Hz, 1H),7.56 (d, J=12.5 Hz, 1H), 3.26-3.13 (m, 2H), 1.53-1.48 (m, 2H), 0.86 (t,J=7.0 Hz, 3H).

Example 4(20):2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)benzamidetrifluoroacetate

LCMS retention Time (min): 0.67;

MS (ESI, Pos.): 336 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.79 (s, 1H), 8.29 (s, 2H), 7.95 (d, J=2.0 Hz, 1H),7.55 (dd, J=8.5 Hz, 1H). 1H), 6.88 (d, J=8.5 Hz, 1H).

Example 4(21):2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-N-ethylbenzamidetrifluoroacetate

LCMS retention time (min): 0.55;

MS (ESI, Pos.): 364 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.96 (s, 1H), 8.37 (s, 2H), 8.30 (t, J=6.0 Hz, 1H),7.96 (d, J=2.5 Hz, 1H), 7.57 (dd, J=11.5, 2.5 Hz. 1H), 6.88 (d, J=11.5Hz, 1H), 5.84 (brs, 2H), 3.25 (qd, J=9.0, 6.0 Hz, 2H), 1.10 (t, J=9.0Hz, 3H).

Example 4(22):1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)phenyl)propan-1-onetrifluoroacetate

HPLC retention time (min): 0.62;

MS (ESI, Pos.): 349 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.97 (s, 1H), 8.37 ($, 2H), 8.33 (s, 1H), 8.25 (d,J=2.0 Hz, 1H), 7.76 (dd, J=9.0, 2.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H),6.46 (br s, 2H), 5.94 (brs, 2H), 3.06 (q, J=7.0 Hz, 2H), 1.10 (t, J=7.0Hz, 3H).

Example 4(23):2-amino-S-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-chloro-N-ethylbenzamidetrifluoroacetate

LCMS retention time (min): 0.59;

MS (ESI, Pos.): 398 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 9.00 (s, 1H), 8.38 (s, 2H), 8.32 (t, J=6.5 Hz, 1H),7.71 (s, 1H), 6.95 (s, 1H), 5.54 (brs, 2H), 3.23 (qd, J=10.0, 6.5 Hz,2H), 1.08 (t, J=10.0 Hz, 3H).

Example 4(24):4-(2-fluoro-5-methoxy-4-nitrophenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-aminetrifluoroacetate

LCMS retention time (min): 0.92;

MS (ESI, Pos.): 371 (M+H)⁺*.

Example 4 (25):4-(4-amino-2-fluoro-5-(trifluoromethyl)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridine-3-amine

In place of4-(4-amino-2-fluoro-5-(methylthio)phenyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-amine,the compound corresponding to it was prepared by a procedure similar tothat described in Example 4, and purified by reverse phase HPLC (columnused: Xtimate C18 (25 mm×150 mm); mobile phase: 0.225% formicacid/water/acetonitrile=75:25 to 45:55) to obtain the compound of thepresent invention having the following physical property value.

LCMS retention time (min): 0.90;

MS (ESI, Pas.): 379 (M+H)⁺;

¹H-NMR (DMSO-do): δ 8.93 (s, 1H), 8.39 (s, 2H), 7.69 (d, J=7.5 Hz, 1H),6.78 (d, J=12.5 Hz, 1H).

Example5:4-(4-amino-2-fluoro-5-(methylsulfinyl)phenyl)-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-aminetrifluoroacetate

The compound (17.2 mg) prepared in Example 4, sodium perboratetetrahydrate (6.16 mg), acetic acid (0.5 mL) and methanol (0.2 mL) weremixed, of which the mixture was stirred at 50° C. for 6 hours. Thereaction solution was purified by reverse phase HPLC (used column: YMCTriart C18 (30 mm×75 mm); mobile phase: 0.1% TFA/water/acetonitrile 95:5to 60:40) to obtain the compound of the present invention (5.0 mg)having the following physical property value.

LCMS retention time (min): 0.50;

MS (ESI, Pos.): 373 (M+H)⁺;

¹H-NMR (DMSO-de): δ 8.99 (s, HI), 8.37 (s, 2H), 7.56 (d, J=8.0 Hz, 1H),6.66 (d, J=12.5 Hz, 1H), 2.79 (s, 3H).

Example 6:2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoicacid

THF (0.2 mL) and methanol (0.1 mL) were added to the compound (20 mg)produced in Example 1, and 2.0 mol/L sodium hydroxide aqueous solution(81 μL) was added dropwise thereto at room temperature, of which themixture was stirred for 3 hours. The reaction solution was neutralizedand purified by reverse phase HPLC (used column: YMC Triart C18 (30mm×75 mm); mobile phase: 0.1% TFA/water/acetonitrile=95:5 to 60:40) toobtain the compound of the present invention (12.1 mg) having physicalproperty value.

LCMS retention time (min): 0.53;

MS (ESI, Pos.): 355 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.97 (s, 1H), 8.35 (s, 2H), 7.93 (d, J=8.5 Hz, 1H),7.23 (br s, 1H), 6.67 (d, J=12.5 Hz, 1H), 5.72 (br s, 2H).

Example 7:4-(4-amino-2-fluoro-5-methoxyphenyl)-7-(3-methyl-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-3-aminetrifluoroacetate

In place of1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,(1-(tert-butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl)boronic acid wassubjected to the same operations as those in Reference Example6→Reference Example 13→Example 2, to obtain the compound of the presentinvention having the following physical property value.

LCMS retention time (min): 0.56;

MS (ESI, Pos.): 355 (M+H)⁺.

Example 8:1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-hydroxyphenyl)ethan-1-onetrifluoroacetate

To 1,3-dimethyl-2-imidazolidinone solution (3 mL) dissolving1-(2-amino-5-(3-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)ethan-1-one(150 mg) prepared in the processes described in Example 3,acetohydroxamic acid (258 mg) and potassium carbonate (618 mg) wereadded, of which the mixture was stirred at 80° C. for 5 hours. Aftercooling it to room temperature, tap water (15 mL) was added thereto, ofwhich the mixture was extracted with ethyl acetate (20 mL), washed withsaturated saline, and then concentrated. The residue obtained therefromwas purified by silica gel column chromatography (Hi-flash NH) (ethylacetate:methanol=100:0 to 50:50), to obtain1-(2-amino-5-(3-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-hydroxyphenyl)ethan-1-one(50 mg).

To this compound (50 mg), methanol (2.0 mL) and methanesulfonic acid (34mg) were added, of which the mixture was stirred at room temperature for64 hours. The precipitate generated by the reaction was collected byfiltration, dissolved in dimethyl sulfoxide and purified by reversephase HPLC (used column: YMC Triart 08 (30 mm×75 mm); mobile phase:0.1%TFA/water/acetonitrile=95:5 to 60:40) to obtain the compound of thepresent invention (23.1 mg) having the following physical propertyvalue.

LCMS retention time (min): 0.55;

MS (ESI, Pos.): 351 (M+H)⁺.

Reference Example 14: 5-bromo-2-chloro-3-fluoroisonicotinonitrile

In place of 2-chloro-4-fluoro-5-iodopyridine,5-bromo-2-chloro-3-fluoropyridine (CAS No. 831203-13-5) was subjected tothe similar operations as those in Reference Example 1→Reference Example2, to obtain the title compound having the following physical propertyvalue.

¹H-NMR (DMSO-do): δ 8.81 (s, 1H).

Reference Example 15;5-(4-amino-2-fluoro-5-methoxyphenyl)-2-chloro-3-fluoroisonicotinonitrile

Under argon atmosphere,5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(CAS No. 1326283-60-6)(70.0 mg),[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (19.0 mg)and 2 mol/L tripotassium phosphate aqueous solution (0.40 mL) were addedto 1,4-dioxane solution (2.0 mL) dissolving the compound (61.0 mg)prepared in Reference Example 14, of which the mixture was stirred at90° C. for 3 hours. After allowing it to cool, to the reaction solution,water was added, of which the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over sodiumsulfate, and concentrated. The residue obtained therefrom was purifiedby silica gel column chromatography (Hi-flash SI) (hexane:ethylacetate=100:0 to 30: 70) to obtain the title compound (45.0 mg) havingthe following physical property value.

MS (ESI, Pos.): 296 (M+H)⁺;

¹H-NMR (CDCl₃): δ 8.41 (s, 1H), 6.76 (d, J=6.5 Hz, 1H), 6.55 (d, J=11.5Hz, 1H), 4.25 (s, 2H), 3.88 (s, 3H).

Reference Example 16:5-(4-amino-2-fluoro-5-methoxyphenyl)-3-fluoro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isonicotinonitrile

Under argon atmosphere,4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(CAS No. 1072944-26-3)(40.0 mg),[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (11.0 mg)and 2 mol/L tripotassium phosphate aqueous solution (0.20 mL) were addedto 1,4-dioxane solution (2.0 mL) dissolving the compound (45.0 mg)produced in Reference Example 15, of which the mixture was stirred at110° C. for 6 hours. After allowing it to cool, to the reactionsolution, water was added, of which the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried oversodium sulfate, and concentrated. The residue obtained therefrom waspurified by silica gel column chromatography (Hi-flash SI) (hexane:ethylacetate 100:0 to 15:85) to obtain the title compound (30.0 mg) havingthe following physical property value.

MS (ESI, Pos.): 412 (M+H)⁺;

¹H-NMR (CDCl₃): δ 8.57 (dd, J=1.5, 0.5 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H),8.23 (d, J=1.0 Hz, 1H), 6.81 (d, J=6.5 Hz, 1H), 6.56 (d, J=11.0 Hz, 1H),5.49-5.44 (m, 1H), 4.19 (s, 2H), 4.13-4.07 (m, 1H), 3.89 (s, 3H),3.79-3.71 (m, 1H), 2.17-2.05 (m, 3H), 1.80-1.62 (m, 3H).

Reference Example 17:4-(4-amino-2-fluoro-5-methoxyphenyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoxazolo[5,4-c]pyridin-3-amine

Under nitrogen atmosphere, potassium tert-butoxide (89.0 mg) was addedto DMF solution (1.0 mL) dissolving acetohydroxamic acid (59 mg) at roomtemperature, of which the mixture was stirred for 30 minutes. To thismixed solution, DMF solution (2.0 mL) dissolving the compound (65 mg)produced in Reference Example 16 was added dropwise, of which themixture was stirred at room temperature for 16 hours. To the reactionsolution, water was added, of which the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried oversodium sulfate, and concentrated. The residue obtained therefrom waspurified by silica gel column chromatography (Hi-flash SI) (hexane:ethylacetate=100:0 to 15:85) to give the title compound (22.0 mg) having thefollowing physical property value.

MS (ESI, Pos.): 425 (M+H)⁺;

¹H-NMR (CDCh): δ 8.56 (s, 1H), 8.42 (s, 1H), 8.31 (d, J=0.5 Hz, 1H),6.76 (d, J=6.5 Hz, 1H), 6.59 (d, J=10.5 Hz, 1H), 5.52-5.47 (m, 1H),4.14-4.08 (m, 1H), 4.33 (s, 2H), 4.15 (s, 2H), 3.87 (s, 3H), 3.79-3.70(m, 1H), 2.16-2.04 (m, 3H), 1.75-1.50 (m, 3H).

Example 9: 4-t4-amino-2-fluoro-5-methoxyphenyl)-7-(1H-pyrazol-4-yl)isoxazolo[5,4-c]pyridin-3-aminehydrochloride

Hydrochloric acid (1.25 mol/L methanol solution) (0.64 mL) was added toTHF solution (1.0 mL) dissolving the compound (20.0 mg) produced inReference Example 17 at room temperature, of which the mixture wasstirred for 3 hours. The reaction solution was concentrated to give thecompound of the present invention (5.8 mg) having the following physicalproperty value.

LCMS retention time (min): 0.66;

MS (ESI, Pos.): 341 (M+H)⁺;

¹H-NMR (CD₃OD): δ 8.45 (s, 2H). 8.24 (d, J=1.0) Hz, 1H), 6.92 (d, J=7.0Hz, 1H), 6.70 (d, J=11.5 Hz, 1H), 3.89 (s, 3H).

Reference Example 18; methyl2-amino-5-(3-amino-7-(1-(((di-tert-butoxyphosphoryl)oxy)methyl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate

Cesium carbonate (6.61 g) and di-tert-butyl-chloromethyl phosphate (1.41mL) were added to DMF solution (41 mL) dissolving the compound (1.49 g)prepared in Example 1, of which the mixture was heated at 50° C. for 5hours. To the reaction solution, saturated aqueous sodium hydrogencarbonate solution was added, of which the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover sodium sulfate and concentrated. The residue obtained therefrom waspurified by silica gel column chromatography (Hi-flash SI) (hexane:ethylacetate=90:10 to 0:100) to give the title compound (1.14 g) having thefollowing physical property value.

LCMS retention time (min): 0.84;

MS (ESI, Pos.): 591 (M+H)⁺.

Example 10: methyl2-amino-5-(3-amino-7-(1-((phosphonooxy)methyl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate

Purified water (6.8 mL) and acetic acid (13.5 mL) were added to thecompound (1.09 g) produced in Reference Example 18, of which the mixturewas stirred at 50° C. overnight. The precipitate deposited by thereaction was collected by filtration. The obtained filtrate was purifiedby reverse phase HPLC (used column: YMC Triart C18 (50 mm×100 mm);mobile phase:0.1% TFA/water/acetonitrile=95:5 to 50:50) and concentratedto give The compound of the present invention (536 mg) having thefollowing physical property value.

LCMS retention time (min): 0.51;

MS (ESI, Pos.): 479 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.99 (s, 1H), 8.63 (s, 1H), 8.35 (s, 1H), 7.94 (d,J=8.5 Hz, 1H), 7.21 (brs, 2H), 6.71 (d, J=12.5 Hz, 1H), 5.91 (d, J=10.0Hz, 2H), 5.75 (brs, 2H), 3.82 (s, 3H).

Examples 10(1) to 10(12)

In place of methyl2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoateprepared in Example 1, the compound corresponding to it was subjected tothe similar procedures as those of Reference Example 18→ Example 10, toobtain the compound of the present invention having the followingphysical property value.

Example 10(1):(4-(4-(5-acetyl-4-amino-2-fluorophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

Cesium carbonate (91.9 mg) and di-tert-butyl-chloromethylphosphate (20μL) were added to DMF solution (0.5 mL) dissolving the compound (24 mg)produced in Example 3, of which the mixture was stirred at roomtemperature for 8 hours. To the reaction solution, tap water was added,of which the mixture was extracted with ethyl acetate. The organic layerwas washed with saturated saline, dried over sodium sulfate andconcentrated. To the obtained residue, dichloromethane (0.30 mL) andtrifluoroacetic acid (0.12 mL) were added, of which the mixture wasstirred at 40° C. overnight. The reaction solution was diluted with DMSOand purified by reverse phase HPLC (used column: YMC Triart C18 (30mm×75 mm); mobile phase: 0.1% TFA/water/acetonitrile=95:5 to 60:40) togive the compound of the present invention (3.9 mg) having the followingphysical property value.

LCMS retention time (min): 0.50;

MS (ESI, Pos.): 463 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.98 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 7.97 (d,J=8.5 Hz, 1H), 7.70 (brs, 2H), 6.65 (d, J=13.0 Hz, 1H), 5.89 (d, J=10.0Hz, 2H), 5.76 (brs, 2H), 2.51 (s, 3H).

Example 10(2): ethyl2-amino-5-(3-amino-7-(1-((phosphonooxy)methyl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate

Cesium carbonate (128 mg) and di-tert-butyl-chloromethylphosphate (27μL) were added to DMF solution (0.5 mL) dissolving the compound (36 mg)produced in Example 4(6), of which the mixture was stirred at roomtemperature overnight. To the reaction solution, tap water was added, ofwhich the mixture was extracted with ethyl acetate. The organic layerwas washed with saturated saline, dried over sodium sulfate andconcentrated. To the obtained residue, dichloromethane (0.30 mL) andtrifluoroacetic acid (0.18 mL) were added, of which the mixture wasstirred at 40° C. for 3.5 hours. The reaction solution was diluted withDMSO and purified by reverse phase HPLC (used column: YMC Triart C18 (30mm×75 mm); mobile phase: 0.1% TFA/water/acetonitrile 95:5 to 60:40) togive the compound of the present invention (15.0 mg) having thefollowing physical property value.

LCMS retention time (min): 0.55;

MS (ESI, Pos.): 493 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.97 (s, 1H), 8.60 (s, 1H), 8.31 (s, 1H), 7.93 (d,J=8.5 Hz, 1H), 7.19 (br s, 2H), 6.67 (d, J=12.5 Hz, 1H), 5.87 (d, J=10.0Hz, 2H), 5.73 (brs, 2H), 4.26 (q, J=7.0 Hz, 2H), 1.27 (t, J=7.0 Hz, 3H).

Example 10(3):(4-(3-amino-4-(4-amino-5-(ethylcarbamoyl)-2-fluorophenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

LCMS retention time (min): 0.50;

MS (ESI, Pos.): 492 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.99 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 8.27 (t,J=5.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.13 (brs, 2H), 6.60 (d, J=12.5Hz, 1H), 5.88 (d, J=10.0 Hz, 2H), 5.65 (brs, 2H), 3.26-3.18 (m, 2H),1.07 (t, J=7.0 Hz, 3H).

Example 10(4):(4-(3-amino-4-(4-amino-2-fluoro-5-(methylthio)phenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

LCMS holding time (minutes): 0.52;

MS (ESI, Pos.): 467 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.96 (s, 1H), 8.60 (s, 1H), 8.32 (s, 1H), 7.40 (d,J=8.5 Hz, 1H), 6.62 (d, J=12.5 Hz, 1H), 5.95 (brs, 2H), 5.88 (d, J=10.0Hz, 2H), 5.64 (s, 2H), 2.32 (s, 3H).

Example 10(5):(4-(3-amino-4-(4-amino-2-fluoro-5-propionylphenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

LCMS holding time (minutes):0.53;

MS(ESI, Pos.): 477 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.98 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 7.99 (d,J=8.5 Hz, 1H), 7.70 (brs, 2H), 6.66 (d, J=12.0 Hz, 1H), 5.88 (d, J=10.0Hz, 2H), 5.75 (brs, 2H), 2.96 (q, J=7.5 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H).

Example 10(6):(4-(4-(3-acetyl-4-aminophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

LCMS holding time (minutes): 0.48;

MS (ESI, Pos.): 445 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.95 (s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 8.19 (d,J=2.0 Hz, 1H), 7.77 (dd, J=8.5, 2.0 Hz, 1H), 7.58 (brs, 2H), 6.92 (d,J=8.5 Hz, 1H), 5.92-5.85 (m, 4H), 2.54 (s, 3H).

Example 10(7):(4-(3-amino-4-(4-amino-2-fluoro-5-(methylsulfonyl)phenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

LCMS holding time (minutes): 0.668;

MS(ESI, Pos.): 499 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 9.00 (s, 1H), 8.63 (s, 1H), 8.35 (s, 1H), 7.74 (d,J=8.0 Hz, 1H), 6.79 (d, J=12.0 Hz, 1H), 6.64 (bis, 2H), 5.91 (d, J=12.0Hz, 2H), 5.83 (brs, 2H), 3.18 (s, 3H).

Example 10(8): acetate or acetic acid solvate of(4-(3-amino-4-f4-amino-5-(ethylcarbamoyl)-2-chlorophenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

By subjecting the compound (421 mg) produced in Example 4 (23) to thesame operation as in Reference Example 18,(4-(3-amino-4-(4-amino-2-chloro-5-(ethylcarbamoyl)phenyl)isoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldi-tert-butyl phosphate (430 mg) was obtained. Acetic acid (19.3 mL) andpurified water (3.4 mL) were added to this compound (379 mg), of whichthe mixture was stirred at 60° C. for 5 hours. The precipitate obtainedtherein was collected by filtration and dried to obtain the compound ofthe present invention (304 mg) having the following physical propertyvalue and being in the form of acetate or acetic acid solvate.

LCMS retention time (min): 0.706;

MS (ESI, Pos.): 508 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 9.01 (s, 1H), 8.64 (s, 1H), 8.36 (s, 1H), 8.33-8.29(m, 1H), 7.70 (s, 1H), 7.01 (brs, 2H), 6.94 (s, 1H), 5.90 (d, J=10.0 Hz,2H), 5.53 (brs, 2H), 3.24-3.18 (m, 2H), 1.91 (s, 3H), 1.07 (t, J=7.0 Hz,3H).

Example 10(9): hydrate of(4-(4-(5-acetyl-4-amino-2-fluorophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate

By subjecting the compound (100 mg) produced in Example 3 to the sameoperation as in Reference Example 18,(4-<4-(5-acetyl-4-amino-2-fluorophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldi-tert-butyl phosphate (112 mg) was obtained. Acetic acid (0.20 mL) andpurified water (0.05 mL) were added to this compound (25 mg), of whichthe mixture was stirred at 60° C. overnight. The precipitate obtainedtherein was collected by filtration and dried to obtain the compound ofthe present invention (18.0 mg) of Example 10(1) having the followingphysical property value and being in a hydrate form. In addition, it wasconfirmed from the DSC and TG analysis on the compound of the presentinvention that it was a hydrate.

LCMS retention time (min): 0.50;

MS (ESI, Pos.): 463 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 8.98 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 7.97 (d,J=8.5 Hz, 1H), 7.70 (brs, 2H), 6.65 (d, J=13.0 Hz, 1H), 5.89 (d, J=10.0Hz, 2H), 5.76 (brs, 2H), 2.51 (s, 3H).

Example 10(10):(4-(4-(5-acetyl-4-amino-2-fluorophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methylmonohydrogenphosphate monopotassium salt

0.25M aqueous potassium acetate solution (0.43 mL, 1 equivalent) wasadded to acetic acid solution (1.25 mL) dissolving the compound (50 mg)prepared in Example 10(1), of which the mixture was stirred at roomtemperature for 8 hours. The obtained suspension was collected byfiltration and dried under reduced pressure to obtain the compound ofthe present invention (43.5 mg) having the following physical propertyvalue.

LCMS retention time (min): 0.49;

MS (ESI, Pos.): 463 (M+H)⁺;

¹H-NMR (DMSO-d₆+CD₃OD): δ 8.94 (s, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 7.99(d, J=8.5 Hz, 1H), 7.70 (brs, 2H), 6.66 (d, J=13.0 Hz, 1H), 5.69 (d,J=9.5 Hz, 2H), 2.52 (s, 3H).

Example 10(11): trifluoroacetate or trifluoroacetic acid solvate ofethyl2-amino-5-(3-amino-7-(1-((phosphonooxy)methyl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate

Cesium carbonate (128 mg) and di-tert-butyl-chloromethyl phosphate (27[L) were added to DMF solution (0.5 mL) dissolving the compound preparedin Example 4(6) (2.00 g), of which the mixture was stirred at roomtemperature overnight. To the reaction solution, tap water was added, ofwhich the mixture was extracted with ethyl acetate. The organic layerwas washed with saturated saline, dried over sodium sulfate andconcentrated. The residue obtained therefrom was purified by silica gelcolumn chromatography (Hi-flash SI) (hexane:ethyl acetate=90:10 to0:100) to obtain ethyl2-amino-5-(3-amino-7-(1-(((di-tert-butoxyphosphoryl)oxy)methyl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate(2.12 g). Purified water (10 mL), ethanol (10 mL) and trifluoroaceticacid (5.3 mL) were sequentially added thereto, of which the mixture wasstirred at 40° C. After 2 hours, ethanol (5 mL) was added thereto, ofwhich the mixture was cooled to room temperature. The precipitateobtained therein was collected by filtration with washing with ethanoland dried under reduced pressure to obtain the compound of the presentinvention (1.81 g) having the following physical property value.

LCMS retention time (min): 0.55;

MS (ESI, Pos.): 493 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ 9.02 (s, 1H), 8.65 (s, 1H), 8.36 (s, 1H), 7.98 (d,J=8.5 Hz, 1H), 7.32 (brs, 2H), 6.70 (d, J=12.5 Hz, 1H), 5.91 (d, J=10.0Hz, 2H), 5.79 (brs, 2H), 4.28 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.0 Hz,314).

Example 10(12): acetate or acetic acid solvate of ethyl2-amino-3-(3-amino-7-(1-((phosphonooxy)methyl)-1H-pyrazol-4-yl)isoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate

Purified water (30 mL) and acetic acid (20 mL) were added to tirecompound (2.13 g) produced in Example 10(2), of which the mixture wasstirred at 60° C. for 4 hours. The solvent was distilled off underreduced pressure and diluted with ethanol (30 mL). The reaction solutionwas stirred overnight and collected by filtration to give tire compoundof the present invention (1.50 g) having the following physical propertyvalue.

LCMS retention time (min): 0.55;

MS (ESI, Pos.): 493 (M+H)⁺;

¹H-NMR (DMSO-de): δ 8.99 (s, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 7.96 (d,J=8.5 Hz, 1H), 7.21 (brs, 2H), 6.69 (d, J=13.0 Hz, 1H). 5.91 (d, J=10.0Hz, 2H), 5.74 (brs, 2H), 4.27 (q, J=7.0 Hz, 2H), 1.92 (s, 3H), 1.29 (t,J=7.0 Hz, 3H).

Reference Example 19: 4-chloro-7-iodoisothiazolo[4,5-c]pyridin-3-amine

Under nitrogen atmosphere, dimethyl sulfoxide was added to sodiumsulfide (138 mg), of which the mixture was stirred for 10 minutes, andthen the compound (500 mg) produced in Reference Example 2 was addedthereto, of which the mixture was stirred at room temperature for 30minutes. After cooling it to 10° C., aqueous ammonia was added thereto,of which the mixture was stirred for 30 minutes. N-chlorosuccinimide(248 mg) was added thereto, of which the mixture was stirred for 30minutes, and further N-chlorosuccinimide (472 mg) was further addedthereto, of which the mixture was stirred for 30 minutes. Saturatedaqueous sodium thiosulfate solution (5 mL) and tap water (15 mL) wereadded thereto, and the resulting precipitate was collected byfiltration. The precipitate was dried at 50° C. for 1.5 hours, dissolvedin ethyl acetate and washed with tap water. It was dried over sodiumsulfate and concentrated to give the title compound (286 mg) having thefollowing physical property value.

LCMS retention time (min): 0.88;

MS (ESI, Pas.): 312 (M+H)⁺.

Reference Example 20:4-bromo-7-iodoisothiazolo[4,5-c]pyridin-3-amine

Under nitrogen atmosphere, propionitrile (2.4 mL) andbromotrimethylsilane (0.61 mL) were added to the compound (240 mg)produced in Reference Example 19, of which the mixture was stirred at100° C. for 20 hours. After cooling it to 0° C., methyl tert-butyl ether(7.2 mL) was added thereto, of which the mixture was stirred for 1.5hours. The resulting precipitate was collected by filtration to give thetitle compound (317 mg) having the following physical property value.

LCMS retention time (min): 0.91;

MS (ESI, Pos.): 356 (M+H)⁺.

Reference Example 21:4-bromo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isothiazolo[4,5-c]pyridin-3-amine

Under nitrogen atmosphere, to a mixture of the compound (384 mg)produced in Reference Example 20,1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(315 mg) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladiumdichloromethane complex (66 mg), 1,4-dioxane (4.6 mL) and 2 mol/Ltripotassium phosphate aqueous solution (1.6 mL) were added, of whichthe mixture was stirred at 105° C. for 29 hours. After cooling it toroom temperature, ethyl acetate and city water were added thereto, ofwhich the mixture was filtered through Celite (trade name). The mixturewas extracted with ethyl acetate and then concentrated. The residueobtained therefrom was purified by silica gel column chromatography(Hi-flash DIOL) (ethyl acetate:hexane=75:25 to 50:50) to give the titlecompound (75.7 mg) having the following physical property value.

LCMS retention time (min): 0.86;

MS (ESI, Pos.): 380 (M+H)⁺.

Example 11:1-(2-amino-5-(3-amino-7-(1H-pyrazol-4-yl)isothiazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)ethan-1-onetrifluoroacetate

Under nitrogen atmosphere, the boronic acid ester (69 mg) produced inReference Example 12(3) and butyl di-1-adamantylphosphine (8.9 mg),palladium acetate (2.8 mg), potassium iodide (2.7 mg) and 2 mol/Ltripotassium phosphate aqueous solution (0.17 mL) were added to NMPsolution (1.25 mL) dissolving the compound (75 mg) produced in ReferenceExample 21, of which the mixture was stirred at 80° C. for 18 hours.After allowing the reaction solution to cool, it was directly purifiedby silica gel column chromatography (Hi-flash DIOL) (ethylacetate:hexane=80:20 to 50:50) to obtain1-(2-amino-5-(3-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrayol-4-yl)isothiazolo[4,5-c]pyridin-4-yl)-4-fluorophenyl)ethan-1-one(13 mg).

To this compound (13 mg), methanol (0.65 mL) and methanesulfonic acid(8.3 mg) were added, of which the mixture was stirred at roomtemperature for 3 hours. After allowed the reaction mixture to cool toroom temperature, triethylamine (8.8 mg) was added thereto, of which themixture was concentrated, and the residue obtained therefrom waspurified by reverse-phase HPLC (used column: YMC Triart C18 (30 mm×75mm); mobile phase: 0.1% TFA/water/acetonitrile=95:5 to 60:40) to givethe compound of the present invention (3.0 mg) having the followingphysical property value.

LCMS retention time (min): 0.60;

MS (ESI, Pos.): 369 (M+H)⁺;

¹H-NMR (DMSO-d₆): δ8.83 (s, 1H), 8.32 (brs, 1H), 8.10 (brs, 1H), 7.94(d, J=8.5 Hz, 1H), 7.69 (brs, 2H), 6.67 (d, J=3.0 Hz, 1H), 5.87 (s, 2H),2.49 (s, 3H).

PHARMACOLOGICAL EXAMPLE Example 12: Effects on THP1-Dual Cells

THP1-Dual cells (Invivogen) were suspended in RPMI medium to prepare2×10⁶ cells/mL of cell suspension. 50 μL of the cell suspensions weredispensed into a 96-well plate, to which 50 μL of 6 to 20,000 nmol/Lcompound solutions were added. After adding the compound, the mixturewas incubated at 37° C. for about 24 hours. After incubation, 10 μL ofcell suspensions were collected from the respective wells, which weremixed with 50 μL of Quanti-luc (Invivogen). Then, the activation of theIRF (Interferon regulatory factor) pathway was measured by detectingluminescence using a microplate reader (Molecular Devices).

EC50 values of the compounds of the present invention shown in therespective Examples are shown below.

TABLE 1 Example EC50 No. (μmol/L) 2 1.93 4 0.09 4(3) 0.95 1 0.18 4(5)0.08 3 0.04 4(16) 1.00 4(6) 0.04 4(7) 0.02 4(8) 0.02 4(9) 0.13 4(15)0.10

Example 13: Activity on THP1-Dual-STING KO Cells

STING gene homozygous deficient THP1-Dual cells (THP1-Dual-STING KOcells (Invivogen) were suspended in RPM1 medium to prepare 2×10⁶cells/mL cell suspension. 50 μL of cell suspensions were dispensed intoa 96-well plate, to which 50 μL of 6 to 20,000 nM compound solutionswere further added, followed by incubation at 37° C. for about 24 hours.10 μL of the cell suspensions were collected from the respective wells,which were mixed with 50 μL of Quanti-luc (Invivogen), and then theactivity of the (RF pathway was measured by detecting luminescence usinga microplate reader.

The compound of the present invention shown in Example 1 showed no IRFactivating effect. Therefore, it was shown that the IRF activatingeffect of the compound of the present invention exemplified in Example 1is based on the agonistic activity on STING by the compound of thepresent invention.

Example 14: Evaluation of IDO1 Inhibitory Activity

The evaluation of IDO1 inhibitory activity was carried out using theIDO1 Fluorogenic Inhibitor Screening Assay Kit (BPS Bioscience).Specifically, IDO1 Fluorogenic Reaction Solution was dissolved, of which180 μL were added to each well. Then, 10 μL of compounds at therespective concentrations of 0.6, 2, 6, 20, 60 and 200 μmol/L were addedthereto. Further, after adding 10 μL of IDO1 His-Tag solution thereto,of which the mixtures were incubated at room temperature for 1 hour, andthen 20 μL of Fluorescence Solution was added thereto, of which themixtures were incubated at 37° C. for 4 hours. After standing them atroom temperature for 10 minutes, the fluorescence was measured using amicroplate reader (excitation: 400 nm, emission: 510 nm).

The compound of the present invention shown in Example 1 did not showany IDO1 inhibitory activity.

Example 15: Evaluation of Inhibitory Activity Against Various Kinases

4 μmol/L of test substance solution (the compound of the presentinvention shown in Example 1) (at 4 times the final concentration) wasprepared by dissolving it to the assay buffer (20 mmol/L HEPES, 0.01%Triton X-100, 1 mmol/L DTT, pH 7.5). 4 μmol/L of substrate/ATP/metalsolution (at 4 times the final concentration) was prepared by dissolvingthem to the kit buffer (20 mmol/L HEPES, 0.01% Triton X-100, 5 mmol/LDTT, pH 7.5). Various kinase solutions at twice the final concentrationwere prepared by dissolving them to the assay buffer. 5 μL of the testsubstance solution, 5 μL of the substrate/ATP/metal solution and 10 μLof the kinase solution were mixed in wells of a polypropylene 384-wellplate, of which the mixture was reacted at room temperature for 1 to 5hours. The reaction was stopped by adding 70 μL of the terminationbuffer (QuickScout Screening Assist MSA; Carna Biosciences). Thesubstrate peptide and phosphorylated peptide in the reaction solutionwere separated and quantified by LabChip system (Perkin Elmer). Thekinase reaction was evaluated by the product ratio (P/(P+S)) calculatedfrom the peak height (S) of the substrate peptide and the peak height(P) of the phosphorylated peptide. The various kinases used forevaluation are as follows:

BTK, KDR, each subtype of PKCα to i, each CDK of CDK2 to 9, FAK, T1E2,RAF1 and BRAF.

The compound of the present invention shown in Example 1 did not showedany significantly inhibit activities against any of the evaluatedkinases.

Example 16: Evaluation of Anti-Tumor Effect in Tumor Model BearingSubcutaneous Mouse Colon Cancer Cell Line MC38

Colon cancer cell line MC38 derived from C57/BL6 mice weresubcutaneously transplanted to right flank of syngeneic mice (C57/BL6,female, 6 weeks old (Charles River Japan)) (herein, the day oftransplantation was Day 0) to prepare tumor mice bearing subcutaneousMC38. Seven days after transplantation, tumor mice bearing subcutaneousMC38 were grouped based on tumor volume, and used as the Vehicle group(n=8) and the compound administration group (3 mg/kg, n=6) shown inExample 1. The changes in tumor volume were continuously measured untilthe 26 days after transplantation (Day 26). The tumor volume wascalculated by the following formula:[Tumor volume(mm³)][major axis (mm)]×[minor axis (mm)]²×0.5

FIG. 1 showed its results.

The compound represented in Example 1 almost completely suppressed thetumor growth at the dose of 3 mg/kg.

Example 17: Evaluation of Anti-Tumor Effect in Tumor Model BearingSubcutaneous Mouse Colon Cancer Cell Line MC38

Colon cancer cell line MC38 derived from C57/BL6 mice weresubcutaneously transplanted to right flank of syngeneic mice (C57/BL6,female, 6 weeks old (Charles River Japan)) (herein, the day oftransplantation was Day 0) to prepare tumor mice bearing subcutaneousMC38. They were grouped based on tumor volume 7 or 8 days aftertransplantation, to which the Vehicle (n=8 or 6) and the respectivecompounds of Examples 10 and 10(1) to 10(6) (1, 1, 1, 10, 3, 1 and 1mg/kg, n=8 or 6) were administered. The changes in tumor volume weremeasured serially until the 28 or 30 days after transplantation (Day 28or 30). The tumor volume was calculated from the formula shown inExample 16.

FIGS. 2 and 3 showed their results.

All the compounds represented in Examples 10 and 10(1) to 10(6)suppressed tumor growth at the above doses. That is, in the groups towhich the respective compounds represented in Examples 10 and 10(1) to10(6) were administered, the median tumor volumes were less than 500 mm³even 30 days after transplantation.

FORMULATION EXAMPLE Formulation Example 1

The following components are mixed in a conventional method and punchedout to obtain 10,000 tablets containing 5 mg of the active ingredientper tablet,

Methyl 2-amino-5-(3-amino-7-(1H-pyrazol-4-yl) 50 gisoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate Carboxymethyleellulosccalcium 20 g Magnesium stearate 10 g Microcrystalline cellulose 970 g

Formulation Example 2

The following components are mixed by a conventional method, then ofwhich the solutions are sterilized by a conventional method, of which 5mL are filled in ampoules and lyophilized by a conventional method toobtain 10,000 ampules containing 20 mg of the active ingredient perampoule.

Methyl 2-amino-5-(3-amino-7-(1H-pyrazol-4-yl) 200 gisoxazolo[4,5-c]pyridin-4-yl)-4-fluorobenzoate Mannitol 20 g Distilledwater 50 L

INDUSTRIAL AVAILABILITY

Since the compound of the present invention has agonistic activity toSTING, a drug containing the compound as an active ingredient is usefulas an agent for suppressing the progression of, suppressing therecurrence of and/or treating cancer or infectious disease.

The invention claimed is: 1.(4-(4-(5-acetyl-4-amino-2-fluorophenyl)-3-aminoisoxazolo[4,5-c]pyridin-7-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate, a pharmaceutically acceptable salt thereof or asolvate thereof.
 2. A pharmaceutically acceptable salt of a compound ofthe structure formula as below:


3. A solvate of a compound of the structure formula as below:


4. A compound of the structure formula as below:


5. A hydrate of a compound of the structure formula as below: